Inhibitors of SARM1

ABSTRACT

The present disclosure provides compounds and methods useful for inhibiting SARM1 and/or treating and/or preventing axonal degeneration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT Application No. PCT/US2021/012333 filed Jan. 6, 2021, which claims the benefit of U.S. Provisional Application Nos. 62/958,178, filed Jan. 7, 2020, and 63/065,736, filed Aug. 14, 2020, which are herein incorporated by reference in their entirety.

BACKGROUND

Axonal degeneration is a hallmark of several neurological disorders including peripheral neuropathy, traumatic brain injury, and neurodegenerative diseases (Gerdts et al., SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science 348 2016, pp. 453-457, hereby incorporated by reference in its entirety). Neurodegenerative diseases and injuries are devastating to both patients and caregivers. Costs associated with these diseases currently exceed several hundred billion dollars annually in the Unites States alone. Since the incidence of many of these diseases and disorders increases with age, their incidence is rapidly increasing as demographics change.

SUMMARY

The present disclosure provides technologies useful, among other things, for treating and/or preventing neurodegeneration (e.g., for reducing axonal degeneration). In some embodiments, provided technologies inhibit SARM1.

In some embodiments, the present disclosure provides certain compounds and/or compositions that are useful in medicine, and particularly for treating neurodegeneration (e.g., for reducing axonal degeneration).

In some embodiments, the present disclosure provides compounds having a structure as set forth in Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; -   R¹ is an optionally substituted group selected from a 3- to     7-membered saturated or partially unsaturated heterocyclic ring     having 1-3 heteroatoms independently selected from oxygen, nitrogen,     and sulfur or a 5- to 6-membered heteroaryl ring having 1-3     heteroatoms independently selected from oxygen, nitrogen, and     sulfur; -   each R^(x) is independently selected from halogen, cyano, OR, SR,     N(R)₂, or an optionally substituted group selected from C₁₋₄     aliphatic, a 3- to 7-membered saturated or partially unsaturated     carbocyclic ring, a 3- to 7-membered saturated or partially     unsaturated heterocyclic ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to     6-membered heteroaryl ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur; -   L is an optionally substituted C₁₋₄ aliphatic chain wherein one or     two carbon atoms in the aliphatic chain are optionally replaced by a     group independently selected from —O—, —N(R)—, —S—, —C(O)—,     —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—,     and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged     bicyclic carbocyclic ring; -   each R is independently hydrogen or an optionally substituted group     selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; or:     -   two R groups, together with the nitrogen atom to which they are         attached, form an optionally substituted 3- to 7-membered         monocyclic heterocyclic ring having 0-2 additional heteroatoms         independently selected from oxygen, nitrogen, and sulfur; -   R² is hydrogen, halogen, N(R)₂, OR, or an optionally substituted     group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl, a     5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, a 8- to     10-membered bicyclic saturated, partially unsaturated or aryl     carbocyclic ring, a 8- to 10-membered bicyclic saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, or a 8- to     10-membered bicyclic heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; and -   n is 0, 1, or 2.

In some embodiments, the present disclosure provides compounds having a structure as set forth in Formula I′:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; -   R¹ is an optionally substituted group selected from a 3- to     7-membered saturated or partially unsaturated heterocyclic ring     having 1-3 heteroatoms independently selected from oxygen, nitrogen,     and sulfur or a 5- to 6-membered heteroaryl ring having 1-3     heteroatoms independently selected from oxygen, nitrogen, and     sulfur; -   each R^(x) is independently selected from halogen, cyano, OR, SR,     N(R)₂, S(O)₂N(R)₂, C(O)OR, C(O)N(R)₂, or an optionally substituted     group selected from C₁₋₄ aliphatic, a 3- to 7-membered saturated or     partially unsaturated carbocyclic ring, a 3- to 7-membered saturated     or partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; -   L is an optionally substituted C₁₋₄ aliphatic chain wherein one or     two carbon atoms in the aliphatic chain are optionally replaced by a     group independently selected from —O—, —N(R)—, —S—, —S(O)₂—, —C(O)—,     —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—,     and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged     bicyclic carbocyclic ring; -   each R is independently hydrogen or an optionally substituted group     selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; or:     -   two R groups, together with the nitrogen atom to which they are         attached, form an optionally substituted 3- to 7-membered         monocyclic heterocyclic ring having 0-2 additional heteroatoms         independently selected from oxygen, nitrogen, and sulfur; -   R² is hydrogen, halogen, N(R)₂, OR, or an optionally substituted     group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl, a     5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, a 8- to     10-membered bicyclic saturated, partially unsaturated or aryl     carbocyclic ring, a 8- to 10-membered bicyclic saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, or a 8- to     10-membered bicyclic heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; and -   n is 0, 1, or 2.

In some embodiments, provided compounds have structures of Formulae I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, I-h-i, I-i, I-i-i, I-j, I-j-i, I-k, I-k-i, I-l, I-l-i, I-m, I-m-i, I-n, I-n-i, I-o, I-o-i, I-p, I-p-i, I-p-ii, I-q, I-q-i, I-r, I-s, I-t, I-u, and I-v, as set forth below.

In some embodiments, one or more compounds of Formula I is provided and/or utilized in a solid form (e.g., a crystal form or an amorphous form).

In some embodiments, the present disclosure provides compositions that comprise and/or deliver a compound of Formula I (e.g., in a form as described herein), a prodrug or active metabolite thereof.

In some embodiments, the present disclosure provides compositions that comprise and/or deliver a compound of Formula I′. In some embodiments, such compositions are pharmaceutical compositions that include at least one pharmaceutically acceptable carrier, diluent or excipient.

In some embodiments, provided SARM1 inhibitors reduce or inhibit binding of NAD+ by SARM1. In some embodiments, provided SARM1 inhibitors bind to SARM1 within a pocket comprising one or more catalytic residues (e.g., a catalytic cleft of SARM1).

In some embodiments, provided compounds and/or compositions inhibit activity of SARM1. Alternatively or additionally, in some embodiments, provided compounds alleviate one or more attributes of neurodegeneration. In some embodiments, the present disclosure provides methods of treating a neurodegenerative disease or disorder associated with axonal degeneration.

In some embodiments, one or more compounds and/or compositions as described herein are useful, for example, in the practice of medicine. In some embodiments, one or more compounds and/or compositions as described herein are useful, for example, to treat, prevent, or ameliorate axonal degeneration (e.g., one or more features or characteristics thereof). In some embodiments, one or more compounds and/or compositions as described herein are useful, for example, to inhibit axonal degeneration, including axonal degeneration that results from reduction or depletion of NAD+. In some embodiments, one or more compounds and/or compositions as described herein are useful, for example, to prevent the axon distal to an axonal injury from degenerating.

In some embodiments, one or more compounds and/or compositions as described herein are useful, for example, to treat one or more neurodegenerative diseases, disorders or conditions selected from the group consisting of neuropathies or axonopathies. In some embodiments, one or more compounds and/or compositions as described herein are useful, for example, to treat a neuropathy or axonopathy associated with axonal degeneration. In some embodiments, a neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In some embodiments, a neuropathy associated with axonal degeneration results from a de novo or somatic mutation. In some embodiments, a neuropathy associated with axonal degeneration is selected from a list contained herein. In some embodiments, a neuropathy or axonopathy is associated with axonal degeneration, including, but not limited to, Parkinson's disease, Parkinsonian syndromes or Parkinson's plus syndromes such as, for example, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), and corticobasal degeneration, Alzheimer's disease, Herpes infection, diabetes, amyotrophic lateral sclerosis (ALS), a demyelinating disease such as, for example, multiple sclerosis, ischemia or stroke, chemical injury, thermal injury, and AIDS.

In some embodiments, subjects to which a compound or composition as described herein is administered may be or comprise subjects suffering from or susceptible to a neurodegenerative disease, disorder or condition. In some embodiments, a neurodegenerative disease, disorder or condition may be or comprise a traumatic neuronal injury. In some embodiments, a traumatic neuronal injury is blunt force trauma, a closed-head injury, an open head injury, exposure to a concussive and/or explosive force, a penetrating injury in or to the brain cavity or innervated region of the body. In some embodiments, a traumatic neuronal injury is a force which causes axons to deform, stretch, crush or sheer.

In some embodiments, provided methods comprise administering a compound described herein to a patient in need thereof. In some such embodiments, the patient is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the patient has a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.

In some embodiments, provided methods comprise administering a composition as described herein to a patient population in need thereof. In some embodiments, the population is drawn from individuals who engage in activities where the potential for traumatic neuronal injury is high. In some embodiments, the population is drawn from athletes who engage in contact sports or other high-risk activities

In some embodiments, the patient is at risk of developing a neurodegenerative disorder. In some embodiments the patient is elderly. In some embodiments, the patient is known to have a genetic risk factor for neurodegeneration.

In certain embodiments, the present disclosure provides compounds that are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure. Compounds provided by this disclosure are also useful for the study of SARM1 function in biological and pathological phenomena and the comparative evaluation of new SARM1 activity inhibitors in vitro or in vivo.

In some embodiments, one or more compounds and/or compositions as described herein are useful, for example, as a method for inhibiting the degradation of neurons derived from a subject. In some embodiments, one or more compounds and/or compositions as described herein are useful for inhibiting the degeneration of a neuron, or a portion thereof, cultured in vitro. In some embodiments, one or more compounds and/or compositions as described herein are useful as stabilizing agents to promote in vitro neuronal survival.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the structure of the SARM1 protein.

DEFINITIONS

Aliphatic; The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” or “cycloaliphatic”) Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle”) refers to a monocyclic C₃-C₈ hydrocarbon or a bicyclic C₇-C₁₀ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene groups and hybrids thereof.

Alkyl; The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched chain or cyclic hydrocarbon group having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms. The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

Alkylene; The term “alkylene” refers to a bivalent alkyl group. In some embodiments, “alkylene” is a bivalent straight or branched alkyl group. In some embodiments, an “alkylene chain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3- to 7-membered ring. The substituents can be on the same or different atoms.

Alkenyl; The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentyl, cyclohexenyl, and cycloheptenyl.

Alkynyl; The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.

Aryl; The term “aryl” refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic carbocyclic or heterocyclic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, tetrahydronaphthyl, imidazolidinyl, imidazolidin-2-one, and the like.

Binding; It will be understood that the term “binding”, as used herein, typically refers to a non-covalent association between or among two or more entities. “Direct” binding involves physical contact between entities or moieties; indirect binding involves physical interaction by way of physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts—including where interacting entities or moieties are studied in isolation or in the context of more complex systems (e.g., while covalently or otherwise associated with a carrier entity and/or in a biological system or cell).

Biological Sample; As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.

Biomarker: The term “biomarker” is used herein to refer to a to an entity, event, or characteristic whose presence, level, degree, type, and/or form, correlates with a particular biological event or state of interest, so that it is considered to be a “marker” of that event or state. To give but a few examples, in some embodiments, a biomarker may be or comprise a marker for a particular disease state, or for likelihood that a particular disease, disorder or condition may develop, occur, or reoccur. In some embodiments, a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof. Thus, in some embodiments, a biomarker is predictive, in some embodiments, a biomarker is prognostic, in some embodiments, a biomarker is diagnostic, of the relevant biological event or state of interest. A biomarker may be or comprise an entity of any chemical class, and may be or comprise a combination of entities. For example, in some embodiments, a biomarker may be or comprise a nucleic acid, a polypeptide, a lipid, a carbohydrate, a small molecule, an inorganic agent (e.g., a metal or ion), or a combination thereof. In some embodiments, a biomarker is a cell surface marker. In some embodiments, a biomarker is intracellular. In some embodiments, a biomarker is detected outside of cells (e.g., is secreted or is otherwise generated or present outside of cells, e.g., in a body fluid such as blood, urine, tears, saliva, cerebrospinal fluid, etc. In some embodiments, a biomarker may be or comprise a genetic or epigenetic signature. In some embodiments, a biomarker may be or comprise a gene expression signature.

In some embodiments, a biomarker may be or comprise a marker for neurodegeneration, or for likelihood that a neurodegenerative disease, disorder or condition may develop, occur, or reoccur. In some embodiments, a biomarker may be or comprise a marker of neurodegeneration a therapeutic outcome, or likelihood thereof. Thus, in some embodiments, a biomarker is predictive, in some embodiments, a biomarker is prognostic, in some embodiments, a biomarker is diagnostic, of a neurodegenerative disease, disorder or condition. In some embodiments changes in biomarker levels can be detected via cerebral spinal fluid (CSF), plasma and/or serum.

In some embodiments, neurodegeneration may be assessed, for example, by detecting an increase and/or decrease in the concentration of neurofilament protein light (NF-L) and/or neurofilament protein heavy (NF-H) (or its phosphorylated form (pNF-H)) contained in the cerebral spinal fluid of a subject. In some embodiments, the incidence and/or progression of neurodegeneration can be assessed via positron emission tomography (PET) with a synaptic vesicle glycoprotein 2a (SV2A) ligand. In some embodiments, a detectable change in constitutive NAD and/or cADPR levels in neurons can be used to assess neurodegeneration.

In some embodiments, a detectable change in one or more neurodegeneration associated proteins in a subject, relative to a healthy reference population can be used as a biomarker of neurodegeneration. Such proteins include, but are not limited to, albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, and/or total-tau. In some embodiments, an increase in cytokines and/or chemokines, including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1, and/or Il6, can be used as a biomarker of neurodegeneration.

Carrier; As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.

Combination therapy; As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

Composition; Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form—e.g., gas, gel, liquid, solid, etc.

Domain; The term “domain” as used herein refers to a section or portion of an entity. In some embodiments, a “domain” is associated with a particular structural and/or functional feature of the entity so that, when the domain is physically separated from the rest of its parent entity, it substantially or entirely retains the particular structural and/or functional feature. Alternatively or additionally, a domain may be or include a portion of an entity that, when separated from that (parent) entity and linked with a different (recipient) entity, substantially retains and/or imparts on the recipient entity one or more structural and/or functional features that characterized it in the parent entity. In some embodiments, a domain is a section or portion of a molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid, or polypeptide). In some embodiments, a domain is a section of a polypeptide; in some such embodiments, a domain is characterized by a particular structural element (e.g., a particular amino acid sequence or sequence motif, α-helix character, β-sheet character, coiled-coil character, random coil character, etc.), and/or by a particular functional feature (e.g., binding activity, enzymatic activity, folding activity, signaling activity, etc.).

Dosage form or unit dosage form; Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.

Dosing regimen or therapeutic regimen; Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

Excipient; as used herein, refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

Heteroaryl; The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, AH quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

Heterocycle; As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur and nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR⁺ (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. Additionally, a heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings (e.g., 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]dioxine, etc.).

Inhibitory agent; As used herein, the term “inhibitory agent” refers to an entity, condition, or event whose presence, level, or degree correlates with decreased level or activity of a target. In some embodiments, an inhibitory agent may act directly (in which case it exerts its influence directly upon its target, for example, by binding to the target); in some embodiments, an inhibitory agent may act indirectly (in which case it exerts its influence by interacting with and/or otherwise altering a regulator of the target, so that level and/or activity of the target is reduced). In some embodiments, an inhibitory agent is one whose presence or level correlates with a target level or activity that is reduced relative to a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known inhibitory agent, or absence of the inhibitory agent in question, etc.).

Neurodegeneration; As used herein, the term “neurodegeneration” refers to a reduction in one or more features, structures, function, or characteristics of a neuron or neuronal tissue. In some embodiments, neurodegeneration is observed as a pathological reduction in an organism. Those skilled in the art will appreciate that neurodegeneration is associated with certain diseases, disorders and conditions, including those that affect humans. In some embodiments, neurodegeneration may be transient (e.g., as sometimes occurs in association with certain infections and/or chemical or mechanical disruptions); in some embodiments, neurodegeneration may be chronic and/or progressive (e.g., as is often associated with certain diseases, disorders or conditions such as, but not limited to, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington disease, or Alzheimer's disease). In some embodiments, neurodegeneration may be assessed, for example, by detecting in a subject an increase in a biomarker associated with neurodegeneration. In some embodiments, neurodegeneration may be assessed, for example, by detecting in a subject a decrease in a biomarker associated with neurodegeneration. Alternatively or additionally, in some embodiments, neurodegeneration may be assessed by magnetic resonance imaging (MRI), biomarkers contained in cerebral spinal fluid, or other biomarkers observed in patients. In some embodiments, neurodegeneration is defined as a score of below 24 on the mini-mental state examination. In some embodiments, neurodegeneration refers to loss of synapses. In some embodiments, neurodegeneration refers to a reduction in neural tissue relating to a traumatic injury (e.g. exposure to an external force which disrupts the integrity of the neural tissue). In some embodiments, neurodegeneration refers to a reduction in peripheral neural tissue. In some embodiments, neurodegeneration refers to a reduction in central nervous tissue.

Oral; The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.

Parenteral; The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

Partially Unsaturated; As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

Patient; As used herein, the term “patient” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient displays one or more symptoms of a disorder or condition. In some embodiments, a patient has been diagnosed with one or more disorders or conditions. In some embodiments, the patient is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.

Pharmaceutical composition; As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

Pharmaceutically acceptable; As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carrier; As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and/or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

Pharmaceutically acceptable salt; The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

Prevent or prevention; As used herein, the terms “prevent” or “prevention”, when used in connection with the occurrence of a disease, disorder, and/or condition, refer to reducing the risk of developing the disease, disorder and/or condition and/or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

Specific; The term “specific”, when used herein with reference to an agent having an activity, is understood by those skilled in the art to mean that the agent discriminates between potential target entities or states. For example, in some embodiments, an agent is said to bind “specifically” to its target if it binds preferentially with that target in the presence of one or more competing alternative targets. In many embodiments, specific interaction is dependent upon the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to that of a reference specific binding agent. In some embodiments, specificity is evaluated relative to that of a reference non-specific binding agent. In some embodiments, the agent or entity does not detectably bind to the competing alternative target under conditions of binding to its target entity. In some embodiments, a binding agent binds with higher on-rate, lower off-rate, increased affinity, decreased dissociation, and/or increased stability to its target entity as compared with the competing alternative target(s).

Subject; As used herein, the term “subject” refers to an organism, typically a mammal (e.g., a human, in some embodiments including prenatal human forms). In some embodiments, a subject is suffering from a relevant disease, disorder or condition. In some embodiments, a subject is susceptible to a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and/or therapy is and/or has been administered.

Substituted or optionally substituted; As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g,

refers to at least

and refers to at least

Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may be substituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substituted with R^(∘); —CH═CHPh, which may be substituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘); —N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘); —N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘); —(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘); —OC(O)(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)(NH)R^(∘); —(CH₂)₀₋₄ S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branched alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted as defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5- to 6-membered heteroaryl ring), a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^(∘), taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by taking two independent occurrences of R^(∘) together with their intervening atoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄ straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●) is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O (“oxo”), ═S, ═NNR*₂, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or —S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selected from hydrogen, C₁₋₆ aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* is selected from hydrogen, C₁₋₆ aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†), —C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂, —C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein each R^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^(†), taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independently halogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Therapeutic agent; As used herein, the phrase “therapeutic agent” in general refers to any agent that elicits a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. In some embodiments, a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.

Treat; As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.

Additionally, unless otherwise stated, in some embodiments, structures depicted herein also include compounds that differ only in the presence of one or more isotopically enriched or isotopically-labeled atoms. The isotopicallydabeled compounds may have one or more atoms replaced by an atom having an atomic mass or mass number usually found in nature. Examples of isotopes present in compounds of formula I or formula I′, and subgenera described herein, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S and ¹⁸F. Certain isotopically-labeled compounds of formula I or formula I′, and subgenera described herein, in addition to being useful as as therapeutic agents, are also useful in drug and/or substrate tissue distribution assays, as analytical tools or as probes in other biological assays. In one aspect of the present invention, tritiated (e.g., ³H) and carbon-14 (e.g., ¹⁴C) isotopes are useful given their ease of detectability. In another aspect of the present invention, replacement of one or more hydrogen atoms with heavier isotopes such as deuterium, (e.g., ²H) can afford certain therapeutic advantages.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Programmed Axonal Degeneration and SARM1

Axonal degeneration is a major pathological feature of neurological diseases such as, but not limited to, Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, inherited neuropathy, traumatic brain injury, and/or glaucoma. Damaged or unhealthy axons are eliminated via an intrinsic self-destruction program that is distinct from traditional cellular death pathways like apoptosis known as Wallerian degeneration. (Gerdts, J., et al., Neuron, 2016, 89, 449-460; Whitmore, A. V. et al., Cell Death Differ., 2003, 10, 260-261). In Wallerian degeneration, a peripheral nerve undergoes selective breakdown of the axon segment distal to an injury, whereas the proximal axon segment and cell body remain intact. This degeneration is characterized, first, by a depletion of nicotinamide mononucleotide adenyltransferase (NMNAT), followed by nicotinamide adenine dinucleotide (NAD+) loss, adenosine tri-phosphate (ATP) loss, neurofilament proteolysis, and finally axonal degradation approximately 8 to 24 hours following injury. (Gerdts, J., et al., Neuron, 2016, 89, 449-460).

NAD+ is a ubiquitous metabolite with critical roles in energy metabolism and cell signaling (Belenkey et al., Trends Biochem., 2007, 32, 12-19; Chiarugi et al., Nat. Rev. Cancer, 2012, 12, 741-752). The homeostatic regulation of NAD+ levels is also responsible for maintaining axonal stability and integrity. Accordingly, manipulations that increase axonal localization of NMNAT 1 confer axonal protection (Babetto et al., Cell Rep., 2010, 3, 1422-1429; Sasaki et al., J. Neurosci., 2009).

In a genome-wide RNAi screen in primary mouse neurons, Sterile Alpha and TIR motif-containing 1 (SARM1) was identified, in which knockdown of SARM1 led to long-lasting protection of sensory neurons against injury-induced axon degeneration (Gerdts et al., J Neurosci, 2013, 33, 13569-13580). SARM1 belongs to the family of cytosolic adaptor proteins, but is unique among its members because it is the most evolutionary ancient adaptor, paradoxically inhibits TLR signaling, and has been identified as the central executioner of the injury-induced axon death pathway (O'Neill, L. A. & Bowie, A. G., Nat. Rev. Immunol., 2007, 7, 353-364; Osterloh, J. M., et al., Science, 2012, 337, 481-484; Gerdts, J., et al., J. Neurosci. 33, 2013, 13569-13580). Activation of SARM1 via axonal injury or forced dimerization of SARM1-TIR domains promotes rapid and catastrophic depletion of Nicotinamide Adenine Dinucleotide (NAD+), followed soon after by axonal degradation, thus highlighting the central role of NAD+ homeostasis in axonal integrity. (Gerdts, J., et al., Science, 2015, 348, 453-457). SARM1 is required for this injury-induced NAD+ depletion both in vitro and in vivo and SARM1 activation triggers axon degeneration locally via NAD(+) destruction (Gerdts et al., et al., Science, 2015 348, 452-457; Sasaki et al., J. Biol. Chem. 2015, 290, 17228-17238; both of which are hereby incorporated by reference in their entireties).

From genetic loss-of-function studies it is clear that SARM1 serves as the central executioner of the axonal degeneration pathway following an injury. Genetic knockout of SARM1 allows for preservation of axons for 14 or more days after nerve transection (Osterloh, J. M., et al., Science, 2012, 337, 481-484; Gerdts, J., et al. J. Neurosci., 2013, 33, 13569-13580) and also improves functional outcomes in mice after traumatic brain injury (Henninger, N. et al., Brain 139, 2016, 1094-1105). In addition to the role of SARM1 in direct axonal injury, SARM1 is also required for axonal degeneration observed in chemotherapy-induced peripheral neuropathy. Loss of SARM1 blocks chemotherapy-induced peripheral neuropathy, both inhibiting axonal degeneration and heightened pain sensitivity that develops after chemotherapeutic vincristine treatment (Geisler et al, Brain, 2016, 139, 3092-3108).

SARM1 contains multiple conserved motifs including SAM domains, ARM/HEAT motifs and a TIR domain (FIG. 1 ) that mediate oligomerization and protein-protein interactions (O'Neill, L. A. & Bowie, A. G., Nat. Rev. Immunol, 2007, 7, 353-364; Tewari, R., et al., Trends Cell Biol, 2010, 20, 470-481; Qiao, F. & Bowie, J. U., Sci. STKE 2005, re7, 2005). TIR domains are commonly found in signaling proteins functioning in innate immunity pathways where they serve as scaffolds for protein complexes (O'Neill, L. A. & Bowie, A. G., Nat. Rev. Immunol., 2007, 7, 353-364). Interestingly, dimerization of SARM1-TIR domains is sufficient to induce axonal degeneration and to rapidly trigger degradation of NAD+ by acting as the NAD+ cleaving enzyme (Milbrandt et al., WO 2018/057989; Gerdts, J., et al., Science, 2015, 348, 453-457). Given the central role of SARM1 in the axonal-degeneration pathway and its identified NADase activity, efforts have been undertaken to identify agents that can regulate SARM1, and potentially act as useful therapeutic agents, for example, to protect against neurodegenerative diseases including peripheral neuropathy, traumatic brain injury, and/or neurodegenerative diseases.

Among other things, the present disclosure provides certain compounds and/or compositions that act as SARM1 inhibitory agents (e.g., as SARM1 inhibitory agents), and technologies relating thereto.

Compounds

In some embodiments, the present disclosure provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; -   R¹ is an optionally substituted group selected from a 3- to     7-membered saturated or partially unsaturated heterocyclic ring     having 1-3 heteroatoms independently selected from oxygen, nitrogen,     and sulfur or a 5- to 6-membered heteroaryl ring having 1-3     heteroatoms independently selected from oxygen, nitrogen, and     sulfur; -   each R^(x) is independently selected from halogen, cyano, OR, SR,     N(R)₂, or an optionally substituted group selected from C₁₋₄     aliphatic, a 3- to 7-membered saturated or partially unsaturated     carbocyclic ring, a 3- to 7-membered saturated or partially     unsaturated heterocyclic ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to     6-membered heteroaryl ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur; -   L is an optionally substituted C₁₋₄ aliphatic chain wherein one or     two carbon atoms in the aliphatic chain are optionally replaced by a     group independently selected from —O—, —N(R)—, —S—, —C(O)—,     —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—,     and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged     bicyclic carbocyclic ring; -   each R is independently hydrogen or an optionally substituted group     selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; or:     -   two R groups, together with the nitrogen atom to which they are         attached, form an optionally substituted 3- to 7-membered         monocyclic heterocyclic ring having 0-2 additional heteroatoms         independently selected from oxygen, nitrogen, and sulfur; -   R² is hydrogen, halogen, N(R)₂, OR, or an optionally substituted     group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl, a     5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, a 8- to     10-membered bicyclic saturated, partially unsaturated or aryl     carbocyclic ring, a 8- to 10-membered bicyclic saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, or a 8- to     10-membered bicyclic heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; and -   n is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound of Formula I′:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; -   R¹ is an optionally substituted group selected from a 3- to     7-membered saturated or partially unsaturated heterocyclic ring     having 1-3 heteroatoms independently selected from oxygen, nitrogen,     and sulfur or a 5- to 6-membered heteroaryl ring having 1-3     heteroatoms independently selected from oxygen, nitrogen, and     sulfur; -   each R^(x) is independently selected from halogen, cyano, OR, SR,     N(R)₂, S(O)₂N(R)₂, C(O)OR, C(O)N(R)₂, or an optionally substituted     group selected from C₁₋₄ aliphatic, a 3- to 7-membered saturated or     partially unsaturated carbocyclic ring, a 3- to 7-membered saturated     or partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; -   L is an optionally substituted C₁₋₄ aliphatic chain wherein one or     two carbon atoms in the aliphatic chain are optionally replaced by a     group independently selected from —O—, —N(R)—, —S—, —S(O)₂—, —C(O)—,     —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—,     and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged     bicyclic carbocyclic ring; -   each R is independently hydrogen or an optionally substituted group     selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; or:     -   two R groups, together with the nitrogen atom to which they are         attached, form an optionally substituted 3- to 7-membered         monocyclic heterocyclic ring having 0-2 additional heteroatoms         independently selected from oxygen, nitrogen, and sulfur; -   R² is hydrogen, halogen, N(R)₂, OR, or an optionally substituted     group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl, a     5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, a 8- to     10-membered bicyclic saturated, partially unsaturated or aryl     carbocyclic ring, a 8- to 10-membered bicyclic saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, or a 8- to     10-membered bicyclic heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; and -   n is 0, 1, or 2.

As defined generally above, Ring A is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, Ring A is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, Ring A is pyrrolyl, furanyl, or thiophenyl. In some embodiments, Ring A is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, Ring A is a group selected from pyrazolyl, imidazolyl, isothiazolyl, and thiazolyl.

In some embodiments, Ring A is a 5-membered heteroaryl ring having 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, Ring A is a group selected from triazolyl and thiadiazolyl.

In some embodiments, Ring A is a 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyridin-2(1H)-onyl.

In some embodiments, Ring A is selected from

In some embodiments. Ring A is selected from

-   wherein R^(x) is an optionally substituted group selected from C₁₋₄     aliphatic, a 3- to 7-membered saturated or partially unsaturated     carbocyclic ring, a 3- to 7-membered saturated or partially     unsaturated heterocyclic ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to     6-membered heteroaryl ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur.

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

wherein:

-   R^(x) on a nitrogen atom is selected from an optionally substituted     group selected from C₁₋₄ aliphatic, a 3- to 7-membered saturated or     partially unsaturated carbocyclic ring, a 3- to 7-membered saturated     or partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; and -   R^(x) on a carbon atom is selected from halogen, cyano, OR, SR,     N(R)₂, or an optionally substituted group selected from C₁₋₄     aliphatic, a 3- to 7-membered saturated or partially unsaturated     carbocyclic ring, a 3- to 7-membered saturated or partially     unsaturated heterocyclic ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to     6-membered heteroaryl ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur.

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In certain particularly preferred embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

As defined generally above, R¹ is an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

In some embodiments, R¹ is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R¹ is an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R¹ is an optionally substituted group selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.

In some embodiments, R¹ is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

In some embodiments, R¹ is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R¹ is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R¹ is an optionally substituted group selected from pyrazolyl, thiazolyl, and thiophenyl ring. In some embodiments, R¹ is an optionally substituted group selected from imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, and thiophenyl ring.

In some embodiments, R¹ is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, R¹ is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R¹ is an optionally substituted group selected from pyridinyl, pyrimidinyl and pyridazinyl.

In some embodiments, R¹ is selected from

In some embodiments, R¹ is selected from

In certain particularly preferred embodiments, R¹ is selected from

As defined generally above for formula I, each R^(x) is independently selected from halogen, cyano, OR, SR, N(R)₂, or an optionally substituted group selected from C₁₋₄ aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. As defined generally above for formula I′, each R^(x) is independently selected from halogen, cyano, OR, SR, N(R)₂, S(O)₂N(R)₂, C(O)OR, C(O)N(R)₂, or an optionally substituted group selected from C₁₋₄ aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

In some embodiments of formula I or formula I′, R^(x) is halogen. In some such embodiments, R^(x) is chloro or bromo. In some embodiments of formula I or formula I′, R^(x) is fluoro.

In some embodiments of formula I or formula I′, R^(x) is cyano.

In some embodiments of formula I or formula I′, R^(x) is OR. In some embodiments of formula I or formula I′, R^(x) is OR, wherein R is selected from hydrogen and optionally substituted C₁₋₆ aliphatic. In some embodiments of formula I or formula I′, R^(x) is OR, wherein R is selected from hydrogen and optionally substituted C₁₋₄ aliphatic. In some embodiments of formula I or formula I′, R^(x) is selected from OH, OCH₃, and OCH₂CH₃.

In some embodiments of formula I or formula I′, R^(x) is SR. In some embodiments of formula I or formula I′, R^(x) is SR, wherein R is selected from hydrogen and optionally substituted C₁₋₆ aliphatic. In some embodiments of formula I or formula I′, R^(x) is SR, wherein R is selected from hydrogen and optionally substituted C₁₋₄ aliphatic. In some embodiments of formula I or formula I′, R^(x) is selected from SH, SCH₃, and SCH₂CH₃.

In some embodiments of formula I or formula I′, R^(x) is N(R)₂. In some embodiments of formula I or formula I′, R^(x) is N(R)₂, wherein R is selected from hydrogen and optionally substituted C₁₋₆ aliphatic. In some embodiments of formula I or formula I′, R^(x) is N(R)₂, wherein R is selected from hydrogen and optionally substituted C₁₋₄ aliphatic. In some embodiments of formula I or formula I′, R^(x) is selected from NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂, and N(CH₂CH₃)₂.

In some embodiments of formula I or formula I′, R^(x) is optionally substituted C₁₋₄ aliphatic. In some embodiments of formula I or formula I′, R^(x) is CH₃, CD₃, or CH₂CH₃. In some embodiments of formula I or formula I′, R^(x) is optionally substituted C₃₋₄ aliphatic. In some such embodiments, R^(x) is selected from tert-butyl,

In some embodiments of formula I or formula I′, R^(x) is

In some embodiments of formula I or formula I′, R^(x) is C₁₋₄ aliphatic optionally substituted with a group selected from halogen, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), —(CH₂)₀₋₄N(R^(∘))₂, —(CH₂)₀₋₄C(O)OR^(∘), and —(CH₂)₀₋₄C(O)NR^(∘) ₂. In some such embodiments, R^(∘) is selected from hydrogen, C₁₋₆ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5- to 6-membered heteroaryl ring), a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two independent occurrences of R^(∘), taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments of formula I or formula I′, R^(x) is C₁₋₄ aliphatic optionally substituted with a group selected from halogen, —R^(∘), —OR^(∘), —N(R^(∘))₂, —C(O)OR^(∘), and —C(O)NR^(∘) ₂. In some embodiments of formula I or formula I′, R^(x) is C₁₋₄ aliphatic optionally substituted with halogen. In some such embodiments, R^(x) is selected from —CH₃, —CF₃, —CHF₂, and CH₂F. In some embodiments of formula I or formula I′, R^(x) is selected from —CH₃, —CD₃, —CF₃, —CHF₂, and CH₂F.

In some embodiments of formula I or formula I′, R^(x) is selected from —CH₂R^(∘), —CH₂OR^(∘), —CH₂N(R^(∘))₂, —CH₂C(O)OR^(∘), and —CH₂C(O)N(R^(∘))₂. In some such embodiments, R^(x) is selected from —CH₂OH, —CH₂OCH₃, —CH₂C(O)NH₂, —CH₂C(O)NHCH₃, and —CH₂C(O)N(CH₃)₂. In some embodiments of formula I or formula I′, R^(x) is CH₂C(O)OR^(∘). In some such embodiments, R^(x) is CO₂CH₃ or CO₂CH₂CH₃.

In some embodiments of formula I or formula I′, R^(x) is C₁₋₄ aliphatic optionally substituted with a group selected from halogen, —R^(∘), —OR^(∘), —N(R^(∘))₂, —C(O)OR^(∘), and —C(O)NR^(∘) ₂.

In some embodiments of formula I′, R^(x) is selected from S(O)₂N(R)₂, C(O)OR, and C(O)N(R)₂. In some embodiments of formula I′, R^(x) is S(O)₂N(R)₂. In some such embodiments, R is hydrogen. In some embodiments of formula I′, R^(x) is SO₂NH₂. In some embodiments of formula I′, R^(x) is C(O)OR. In some such embodiments, R is selected from hydrogen, CH₃, and CH₂CH₃. In some embodiments of formula I′, R^(x) is C(O)OCH₂CH₃. In some embodiments of formula I′, R^(x) is C(O)N(R)₂. In some such embodiments, R is hydrogen or CH₃. In some embodiments of I′, R^(x) is C(O)NH₂ or R^(x) is C(O)N(CH₃)₂. In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 5- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 5- to 7-membered saturated carbocyclic ring. In some such embodiments, R^(x) is selected from optionally substituted cyclopentyl or cyclohexyl.

In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 3- to 4-membered saturated heterocyclic ring having 1 heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 5- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 5- to 7-membered saturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, R^(x) is selected from optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.

In some embodiments of formula I or formula I′, R^(x) is optionally substituted phenyl.

In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, R^(x) is selected from optionally substituted pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, and thiazolyl.

In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments of formula I or formula I′, R^(x) is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some such embodiments, R^(x) is selected from optionally substituted pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

As defined generally above for formula I, L is an optionally substituted Cu 4 aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

As defined generally above for formula I′, L is an optionally substituted C₁₋₄ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —S(O)₂—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

In some embodiments of formula I or formula I′, L is an optionally substituted C₁₋₂ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring. In some embodiments of formula I or formula I′, L is an optionally substituted C₁₋₂ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring. In some embodiments of formula I or formula I′, L is an optionally substituted C₁₋₂ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(H)—, —S—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

In some embodiments of formula I or formula I′, L is an optionally substituted C₃₋₄ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring. In some embodiments of formula I or formula I′, L is an optionally substituted C₃₋₄ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring. In some embodiments of formula I or formula I′, L is an optionally substituted C₃₋₄ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(H)—, —S—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

In some embodiments of formula I or formula I′, L is an optionally substituted C₁₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(R)—, —S—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

In some embodiments of formula I or formula I′, L is an optionally substituted C₁₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(R)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring. In some embodiments of formula I or formula I′, L is an optionally substituted C₁₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(H)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

In some embodiments of formula I or formula I′, L is an optionally substituted C₃₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(R)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring. In some embodiments of formula I or formula I′, L is an optionally substituted C₃₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(H)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

In some embodiments of formula I or formula I′, L is selected from

In some embodiments of formula I′, L is selected from

In certain particularly preferred embodiments of formula I or formula I′, L is selected from

In certain particularly preferred embodiments of formula I or formula I′, L is selected from

As defined generally above, each R is independently hydrogen or an optionally substituted group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or two R groups, together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur.

In some embodiments, R is optionally substituted C₁₋₆ aliphatic. In some embodiments, R is C₁₋₆ aliphatic optionally substituted with oxo and OR^(∘), wherein R^(∘) is C₁₋₆ aliphatic. In some such embodiments, R is —C(O)OtBu.

In some embodiments, R is C₁₋₆ aliphatic. In some such embodiments, R is methyl or ethyl.

In some embodiments, R is selected from hydrogen and optionally substituted C₁₋₆ aliphatic. In some such embodiments, R is selected from hydrogen, methyl or ethyl.

As defined generally above, R² is hydrogen, halogen, N(R)₂, OR, or an optionally substituted group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

In some embodiments, R² is hydrogen. In some embodiments, R² is halogen, N(R)₂, OR, or an optionally substituted group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

In some embodiments, R² is halogen. In some embodiments, R² is N(R)₂. In some such embodiments, R² is NH₂. In some embodiments, R² is OR. In some such embodiments, R² is OH.

In some embodiments, R² is optionally substituted C₁₋₆ aliphatic. In some such embodiments, R² is an optionally substituted group selected from cyclopentyl or cyclohexyl. In some embodiments, R² is C₁₋₆ aliphatic. In some embodiments, R² is methyl. In some embodiments, R² is ethyl. In some embodiments, R² is tert-butyl. In some embodiments, R² is neopentyl (i.e., 2,2-dimethylpropyl). In some embodiments, R² is cyclohexyl.

In some embodiments, R² is optionally substituted phenyl.

In some embodiments, R² is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R² is an optionally substituted 3-membered saturated heterocyclic ring having 1 heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, R² is an optionally substituted 4-membered saturated heterocyclic ring having 1 heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, R² is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R² is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R² is an optionally substituted group selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.

In some embodiments, R² is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R² is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R² is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, R² is an optionally substituted group selected from thiophenyl, pyrazolyl, and imidazolyl.

In some embodiments, R² is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, R² is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some such embodiments, R² is an optionally substituted group selected from pyridinyl or pyrimidinyl.

In some embodiments, R² is an optionally substituted 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring. In some embodiments, R² is an optionally substituted 9-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring. In some such embodiments, R² is optionally substituted 2,3-dihydro-1H-indenyl. In some embodiments, R² is an optionally substituted 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring. In some such embodiments, R² is an optionally substituted group selected from 1,2,3,4-tetrahydronaphthalenyl and naphthalenyl.

In some embodiments, R² is an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R² is an optionally substituted 9-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R² is an optionally substituted 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, R² is an optionally substituted group selected from chromanyl, isochromanyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, and 2H-benzo[b][1,4]oxazin-3(4H)-onyl.

In some embodiments, R² is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R² is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some such embodiments, R² is an optionally substituted group selected from indolyl, benzopyrazolyl, benzimidazolyl, and imidazo[1,2-a]pyridinyl.

In some embodiments, R² is selected from the group consisting of

In some embodiments, R² is selected from the group consisting of

In certain particularly preferred embodiments, R² is selected from

In some embodiments, R² is selected from

In some embodiments of Formula I or Formula I′, L is

Accordingly, in some embodiments, the present disclosure provides a compound of Formula I-a:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R^(x), R¹, R², R, and n is as defined above and described herein.

In some embodiments of Formula I or Formula I′, L is

Accordingly, in some embodiments, the present disclosure provides a compound of Formula I-b:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R^(x), R¹, R², R, and n is as defined above and described herein.

In some embodiments of Formula I or Formula I′, R¹ is

Accordingly, in some embodiments, the present disclosure provides a compound of Formula I-c:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R^(x), L, R², R, and n is as defined above and described herein.

In some embodiments of Formula I or Formula I′, R¹ is

Accordingly, in some embodiments, the present disclosure provides a compound of Formula I-d:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R^(x), L, R², R, and n is as defined above and described herein.

In some embodiments of Formula I or Formula I′, Ring A is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Accordingly, in some embodiments, the present disclosure provides a compound of Formulae I-e, I-f, I-g, I-h, I-i, I-j, I-k, I-l, I-m, I-n, or I-o:

or a pharmaceutically acceptable salt thereof, wherein each of L, R¹, R², and R is as defined above and described herein.

In some embodiments of Formula I or Formula I′, L is

Accordingly, in some embodiments, the present disclosure provides a compound of Formula I-p:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R^(x), R¹, R², R, and n is as defined above and described herein.

In some embodiments, the present disclosure provides a compound of Formulae

or a pharmaceutically acceptable salt thereof, wherein each of R^(x), R¹, R², and R is as defined above and described herein.

In some embodiments, the present disclosure provides a compound of Formulae I-a-i, I-b-i, I-c-i, I-d-i, I-e-i, I-f-i, I-g-i, I-h-i, I-i-i, I-j-i, I-k-i, I-l-i, I-m-i, I-n-i, I-o-i, I-p-i, or I-p-ii:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R^(x), L, R¹, R², and n is as defined above and described herein.

In some embodiments, the present disclosure provides a compound of Formulae I-q or I-q-i:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², and R is as defined above and described herein.

In some embodiments of any of Formulae I, I-b, I-b-i, I-c, or I-c-i, Ring A is not

In some embodiments of any of Formulae I, I-b, or I-b-i, Ring A is not

In some embodiments of Formula I-e or Formula I-e-i, L is not

In some embodiments of Formula I-h or Formula I-h-i, L is not

In some embodiments of any of Formulae I, I-b, I-e, I-e-i, I-h, or I-h-i, R¹ is not

In some embodiments, the present disclosure provides a compound selected from:

Example Structure 1

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound selected from

Example Structure 19

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or a pharmaceutically acceptable salt thereof.

In certain particularly preferred embodiments, the present disclosure provides a compound selected from:

Example Structure 19

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound selected from:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound selected from:

Example Structure 27

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or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides a compound according to the following embodiments:

Embodiment 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; -   R¹ is an optionally substituted group selected from a 3- to     7-membered saturated or partially unsaturated heterocyclic ring     having 1-3 heteroatoms independently selected from oxygen, nitrogen,     and sulfur or a 5- to 6-membered heteroaryl ring having 1-3     heteroatoms independently selected from oxygen, nitrogen, and     sulfur; -   each R^(x) is independently selected from halogen, cyano, OR, SR,     N(R)₂, or an optionally substituted group selected from C₁₋₄     aliphatic, a 3- to 7-membered saturated or partially unsaturated     carbocyclic ring, a 3- to 7-membered saturated or partially     unsaturated heterocyclic ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to     6-membered heteroaryl ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur; -   L is an optionally substituted C₁₋₄ aliphatic chain wherein one or     two carbon atoms in the aliphatic chain are optionally replaced by a     group independently selected from —O—, —N(R)—, —S—, —C(O)—,     —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—,     and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged     bicyclic carbocyclic ring; -   each R is independently hydrogen or an optionally substituted group     selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; or:     -   two R groups, together with the nitrogen atom to which they are         attached, form an optionally substituted 3- to 7-membered         monocyclic heterocyclic ring having 0-2 additional heteroatoms         independently selected from oxygen, nitrogen, and sulfur; -   R² is hydrogen, halogen, N(R)₂, OR, or an optionally substituted     group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl, a     5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, a 8- to     10-membered bicyclic saturated, partially unsaturated or aryl     carbocyclic ring, a 8- to 10-membered bicyclic saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, or a 8- to     10-membered bicyclic heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; and -   n is 0, 1, or 2.

Embodiment 2. The compound according to embodiment 1, wherein Ring A is a 6-membered heteroaryl ring having 1-2 nitrogen atoms.

Embodiment 3. The compound according to embodiment 1, wherein Ring A is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 4. The compound according to embodiment 3, wherein Ring A is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 5. The compound according to embodiment 3, wherein Ring A is a 5-membered heteroaryl ring having 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 6. The compound according to embodiment 1, wherein Ring A is selected from

Embodiment 7. The compound according to embodiment 6, wherein Ring A is selected from

Embodiment 7a. The compound according to embodiment 6, wherein Ring A is selected from

Embodiment 8. The compound according to embodiment 1, wherein Ring A is selected from

Embodiment 9. The compound according to embodiment 1, wherein Ring A is selected from

-   wherein R^(x) is an optionally substituted group selected from C₁₋₄     aliphatic, a 3- to 7-membered saturated or partially unsaturated     carbocyclic ring, a 3- to 7-membered saturated or partially     unsaturated heterocyclic ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to     6-membered heteroaryl ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur.

Embodiment 10. The compound according to embodiment 1, wherein Ring A is selected from

Embodiment 11. The compound according to embodiment 1, wherein Ring A is selected from

wherein:

-   R^(x) on a nitrogen atom is selected from an optionally substituted     group selected from C₁₋₄ aliphatic, a 3- to 7-membered saturated or     partially unsaturated carbocyclic ring, a 3- to 7-membered saturated     or partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; and -   R^(x) on a carbon atom is selected from halogen, cyano, OR, SR,     N(R)₂, or an optionally substituted group selected from C₁₋₄     aliphatic, a 3- to 7-membered saturated or partially unsaturated     carbocyclic ring, a 3- to 7-membered saturated or partially     unsaturated heterocyclic ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to     6-membered heteroaryl ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur.

Embodiment 12. The compound according to any one of embodiments 1-11, wherein R^(x) is halogen.

Embodiment 13. The compound according to any one of embodiments 1-11, wherein R^(x) is cyano.

Embodiment 14. The compound according to any one of embodiments 1-11, wherein R^(x) is OR.

Embodiment 15. The compound according to any one of embodiments 1-11, wherein R^(x) is SR.

Embodiment 16. The compound according to any one of embodiments 1-11, wherein R^(x) is N(R)₂.

Embodiment 17. The compound according to any one of embodiments 14-16, wherein R is selected from hydrogen and optionally substituted C₁₋₆ aliphatic.

Embodiment 18. The compound according to embodiment 17, wherein R is selected from hydrogen and optionally substituted C₁₋₄ aliphatic.

Embodiment 19. The compound according to any one of embodiments 14, 17, and 18, wherein R^(x) is OH, OCH₃, and OCH₂CH₃.

Embodiment 20. The compound according to any one of embodiments 15, 17, and 18, wherein R^(x) is SH, SCH₃, and SCH₂CH₃.

Embodiment 21. The compound according to any one of embodiments 16-18, wherein R^(x) is selected from NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂, and N(CH₂CH₃)₂.

Embodiment 22. The compound according to any one of embodiments 1-11, wherein R^(x) is optionally substituted C₁₋₄ aliphatic.

Embodiment 23. The compound according to embodiment 22, wherein R^(x) is optionally substituted C₃₋₄ aliphatic.

Embodiment 24. The compound according to embodiment 23, wherein R^(x) is selected from tert-butyl,

Embodiment 25. The compound according to embodiment 22, wherein R^(x) is C₁₋₄ aliphatic optionally substituted with a group selected from halogen, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), —(CH₂)₀₋₄N(R^(∘))₂, —(CH₂)₀₋₄C(O)OR^(∘), and —(CH₂)₀₋₄C(O)NR^(∘) ₂.

Embodiment 26. The compound according to embodiment 25, wherein R^(∘) is selected from hydrogen, C₁₋₆ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5- to 6-membered heteroaryl ring), a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two independent occurrences of R^(∘), taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Embodiment 27. The compound according to embodiment 22, wherein R^(x) is C₁₋₄ aliphatic optionally substituted with a group selected from halogen, —R^(∘), —OR^(∘), —N(R^(∘))₂, —C(O)OR^(∘), and —C(O)NR^(∘) ₂.

Embodiment 28. The compound according to embodiment 22, wherein R^(x) is C₁₋₄ aliphatic optionally substituted with halogen.

Embodiment 29. The compound according to embodiment 28, wherein R^(x) is selected from —CH₃, —CF₃, —CHF₂, and CH₂F.

Embodiment 29a. The compound according to embodiment 28, wherein R^(x) is selected from —CH₃, —CD₃, —CF₃, —CHF₂, and CH₂F.

Embodiment 30. The compound according to embodiment 22, wherein R^(x) is selected from —CH₂R^(∘), —CH₂OR^(∘), —CH₂N(R^(∘))₂, —CH₂C(O)OR^(∘), and —CH₂C(O)N(R^(∘))₂.

Embodiment 31. The compound according to embodiment 30, wherein R^(x) is selected from —CH₂OH, —CH₂OCH₃, —CH₂C(O)NH₂, —CH₂C(O)NHCH₃, and —CH₂C(O)N(CH₃)₂.

Embodiment 32. The compound according to any one of embodiments 1-31, wherein R¹ is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 33. The compound according to embodiment 32, wherein R¹ is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 34. The compound according to embodiment 33, wherein R¹ is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur

Embodiment 35. The compound according to embodiment 32, wherein R¹ is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms.

Embodiment 36. The compound according to embodiment 35, wherein R¹ is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms.

Embodiment 37. The compound according to embodiment 32, wherein R¹ is selected from

Embodiment 38. The compound according to embodiment 37, wherein R¹ is selected from

Embodiment 39. The compound according to any one of embodiments 1-38, wherein L is an optionally substituted C₁₋₂ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 40. The compound according to embodiment 39, wherein L is an optionally substituted C₁₋₂ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 41. The compound according to embodiment 38 or 39, wherein L is an optionally substituted C₁₋₂ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(H)—, —S—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 42. The compound according to any one of embodiments 1-38, wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 43. The compound according to embodiment 42, wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 44. The compound according to embodiment 42 or 43, wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(H)—, —S—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 45. The compound according to any one of embodiments 1-38, wherein L is an optionally substituted C₁₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(R)—, —S—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 46. The compound according to embodiment 45, wherein L is an optionally substituted C₁₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(R)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 47. The compound according to embodiment 45 or 46, wherein L is an optionally substituted C₁₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(H)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 48. The compound according to embodiment 45 or 46, wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(R)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 49. The compound according to embodiment 48, wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(H)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 50. The compound according to any one of embodiments 1-38, wherein L is selected from

Embodiment 50a. The compound according to any one of embodiments 1-38, wherein L is selected from

Embodiment 51. The compound according to embodiment 50, wherein L is selected from

Embodiment 51a. The compound according to embodiment 50, wherein L is selected from

Embodiment 52. The compound according to any one of embodiments 1-51a, wherein R is hydrogen.

Embodiment 53. The compound according to any one of embodiments 1-51a, wherein R is —CH₃.

Embodiment 54. The compound according to any one of embodiments 1-51a, wherein R is optionally substituted C₁₋₆ aliphatic.

Embodiment 55. The compound according to embodiment 54, wherein R is aliphatic optionally substituted with oxo and OR^(∘).

Embodiment 56. The compound according to embodiment 55, wherein R^(∘) is C₁₋₆ aliphatic.

Embodiment 57. The compound according to embodiment 54, wherein R is methyl or ethyl.

Embodiment 58. The compound according to any one of embodiments 1-57, wherein R² is hydrogen.

Embodiment 59. The compound according to any one of embodiments 1-57, wherein R² is halogen, N(R)₂, OR, or an optionally substituted group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 60. The compound according to embodiment 59, wherein R² is N(R)₂.

Embodiment 61. The compound according to embodiment 60, wherein R is NH₂.

Embodiment 62. The compound according to embodiment 59, wherein R² is optionally substituted C₁₋₆ aliphatic.

Embodiment 63. The compound according to embodiment 62, wherein R² is methyl or ethyl.

Embodiment 64. The compound according to embodiment 59, wherein R² is optionally substituted cyclohexyl.

Embodiment 65. The compound according to embodiment 59, wherein R² is optionally substituted phenyl.

Embodiment 66. The compound according to embodiment 59, wherein R² is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 67. The compound according to embodiment 66, wherein R² is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 68. The compound according to embodiment 66 or 67, wherein R² is an optionally substituted group selected from thiophenyl, pyrazolyl, and imidazolyl.

Embodiment 69. The compound according to embodiment 66, wherein R² is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms.

Embodiment 70. The compound according to embodiment 69, wherein R² is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms.

Embodiment 71. The compound according to embodiment 70, wherein R² is an optionally substituted group selected from pyridinyl or pyrimidinyl.

Embodiment 72. The compound according to embodiment 59, wherein R² is an optionally substituted 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring.

Embodiment 73. The compound according to embodiment 72, wherein R² is an optionally substituted 9-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring.

Embodiment 74. The compound according to embodiment 73, wherein R² is optionally substituted 2,3-dihydro-1H-indenyl.

Embodiment 75. The compound according to embodiment 72, wherein R² is an optionally substituted 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring.

Embodiment 76. The compound according to embodiment 75, wherein R² is optionally substituted group selected from 1,2,3,4-tetrahydronaphthalenyl or naphthalenyl.

Embodiment 77. The compound according to embodiment 59, wherein R² is an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 78. The compound according to embodiment 77, wherein R² is an optionally substituted 9-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 79. The compound according to embodiment 77, wherein R² is an optionally substituted 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 80. The compound according to embodiment 79, wherein R² is an optionally substituted group selected from chromanyl, isochromanyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, and 2H-benzo[b][1,4]oxazin-3(4H)-onyl.

Embodiment 81. The compound according to embodiment 59, wherein R² is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 82. The compound according to embodiment 81, wherein R² is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 83. The compound according to embodiment 81 or 82, wherein R² is an optionally substituted group selected from indolyl, benzopyrazolyl, benzimidazolyl, and imidazo[1,2-a]pyridinyl.

Embodiment 84. The compound according to embodiment 59, wherein R² is

selected from the group consisting of

Embodiment 84a. The compound according to embodiment 59, wherein R² is

selected from the group consisting of

Embodiment 85. The compound according to embodiment 84, wherein R² is selected from

Embodiment 85a. The compound according to embodiment 84a, wherein R² is selected from

Embodiment 86. The compound according to embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 87. The compound according to embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 88. The compound according to embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 89. The compound according to embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 90. The compound according to embodiment 1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

Embodiment 90a. The compound according to embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 91. The compound according to embodiment 1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

Embodiment 91a. The compound according to embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 92. A pharmaceutical composition comprising a compound according to any one of embodiments 1-91a and a pharmaceutically acceptable carrier.

Embodiment 93. A method comprising a step of:

administering a compound according to any one of embodiments 1-91a to a subject who (i) has a condition characterized by axonal degeneration or (ii) is at risk of developing a condition characterized by axonal degeneration.

Embodiment 94. A method of treating or preventing axonal degeneration comprising administering to a subject in need thereof a compound according to any one of embodiments 1-91a.

Embodiment 95. A method of inhibiting SARM1 comprising contacting a biological sample with a compound according to any one of embodiments 1-91a.

Embodiment 96. A compound of Formula I′:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; -   R¹ is an optionally substituted group selected from a 3- to     7-membered saturated or partially unsaturated heterocyclic ring     having 1-3 heteroatoms independently selected from oxygen, nitrogen,     and sulfur or a 5- to 6-membered heteroaryl ring having 1-3     heteroatoms independently selected from oxygen, nitrogen, and     sulfur; -   each R^(x) is independently selected from halogen, cyano, OR, SR,     N(R)₂, S(O)₂N(R)₂, C(O)OR, C(O)N(R)₂, or an optionally substituted     group selected from C₁₋₄ aliphatic, a 3- to 7-membered saturated or     partially unsaturated carbocyclic ring, a 3- to 7-membered saturated     or partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; -   L is an optionally substituted C₁₋₄ aliphatic chain wherein one or     two carbon atoms in the aliphatic chain are optionally replaced by a     group independently selected from —O—, —N(R)—, —S—, —S(O)₂—, —C(O)—,     —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—,     and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged     bicyclic carbocyclic ring; -   each R is independently hydrogen or an optionally substituted group     selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; or:     -   two R groups, together with the nitrogen atom to which they are         attached, form an optionally substituted 3- to 7-membered         monocyclic heterocyclic ring having 0-2 additional heteroatoms         independently selected from oxygen, nitrogen, and sulfur; -   R² is hydrogen, halogen, N(R)₂, OR, or an optionally substituted     group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl, a     5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, a 8- to     10-membered bicyclic saturated, partially unsaturated or aryl     carbocyclic ring, a 8- to 10-membered bicyclic saturated or     partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, or a 8- to     10-membered bicyclic heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; and -   n is 0, 1, or 2.

Embodiment 97. The compound according to embodiment 96, wherein Ring A is a 6-membered heteroaryl ring having 1-2 nitrogen atoms.

Embodiment 98. The compound according to embodiment 96, wherein Ring A is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 99. The compound according to embodiment 98, wherein Ring A is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 100. The compound according to embodiment 98, wherein Ring A is a 5-membered heteroaryl ring having 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 101. The compound according to embodiment 96, wherein Ring A is selected from

Embodiment 102. The compound according to embodiment 101, wherein Ring A is selected from

Embodiment 103. The compound according to embodiment 101, wherein Ring A is selected from

Embodiment 104. The compound according to embodiment 96, wherein Ring A is selected from

Embodiment 105. The compound according to embodiment 96, wherein Ring A is selected from

-   wherein R^(x) is an optionally substituted group selected from C₁₋₄     aliphatic, a 3- to 7-membered saturated or partially unsaturated     carbocyclic ring, a 3- to 7-membered saturated or partially     unsaturated heterocyclic ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to     6-membered heteroaryl ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur.

Embodiment 106. The compound according to embodiment 96, wherein Ring A is selected from

Embodiment 107. The compound according to embodiment 96, wherein Ring A is selected from

wherein:

-   R^(x) on a nitrogen atom is selected from an optionally substituted     group selected from C₁₋₄ aliphatic, a 3- to 7-membered saturated or     partially unsaturated carbocyclic ring, a 3- to 7-membered saturated     or partially unsaturated heterocyclic ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur, phenyl,     and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms     independently selected from oxygen, nitrogen, and sulfur; and -   R^(x) on a carbon atom is selected from halogen, cyano, OR, SR,     N(R)₂, or an optionally substituted group selected from C₁₋₄     aliphatic, a 3- to 7-membered saturated or partially unsaturated     carbocyclic ring, a 3- to 7-membered saturated or partially     unsaturated heterocyclic ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur, phenyl, and a 5- to     6-membered heteroaryl ring having 1-3 heteroatoms independently     selected from oxygen, nitrogen, and sulfur.

Embodiment 108. The compound according to any one of embodiments 96-107, wherein R^(x) is halogen.

Embodiment 109. The compound according to any one of embodiments 96-107, wherein R^(x) is cyano.

Embodiment 110. The compound according to any one of embodiments 96-107, wherein R^(x) is OR.

Embodiment 111. The compound according to any one of embodiments 96-107, wherein R^(x) is SR.

Embodiment 112. The compound according to any one of embodiments 96-107, wherein R^(x) is N(R)₂.

Embodiment 113. The compound according to any one of embodiments 110-112, wherein R is selected from hydrogen and optionally substituted C₁₋₆ aliphatic.

Embodiment 114. The compound according to embodiment 113, wherein R is selected from hydrogen and optionally substituted C₁₋₄ aliphatic.

Embodiment 115. The compound according to any one of embodiments 110, 113, and 114, wherein R^(x) is OH, OCH₃, and OCH₂CH₃.

Embodiment 116. The compound according to any one of embodiments 111, 113, and 114, wherein R^(x) is SH, SCH₃, and SCH₂CH₃.

Embodiment 117. The compound according to any one of embodiments 112-114, wherein R^(x) is selected from NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂, and N(CH₂CH₃)₂.

Embodiment 118. The compound according to any one of embodiments 96-107, wherein R^(x) is optionally substituted C₁₋₄ aliphatic.

Embodiment 119. The compound according to embodiment 118, wherein R^(x) is optionally substituted C₃₋₄ aliphatic.

Embodiment 120. The compound according to embodiment 119, wherein R^(x) is selected from tert-butyl,

Embodiment 121. The compound according to embodiment 118, wherein R^(x) is C₁₋₄ aliphatic optionally substituted with a group selected from halogen, —(CH₂)₀₋₄R^(∘), —(CH₂)₀₋₄OR^(∘), —(CH₂)₀₋₄N(R^(∘))₂, —(CH₂)₀₋₄C(O)OR^(∘), and —(CH₂)₀₋₄C(O)NR^(∘) ₂.

Embodiment 122. The compound according to embodiment 121, wherein R^(∘) is selected from hydrogen, C₁₋₆ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5- to 6-membered heteroaryl ring), a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two independent occurrences of R^(∘), taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Embodiment 123. The compound according to embodiment 118, wherein R^(x) is C₁₋₄ aliphatic optionally substituted with a group selected from halogen, —R^(∘), —OR^(∘), —N(R^(∘))₂, —C(O)OR^(∘), and —C(O)NR^(∘) ₂.

Embodiment 124. The compound according to embodiment 118, wherein R^(x) is C₁₋₄ aliphatic optionally substituted with halogen.

Embodiment 125. The compound according to embodiment 124, wherein R^(x) is selected from —CH₃, —CF₃, —CHF₂, and CH₂F.

Embodiment 126. The compound according to embodiment 124, wherein R^(x) is selected from —CH₃, —CD₃, —CF₃, —CHF₂, CH₂F, CH₂CH₃.

Embodiment 127. The compound according to embodiment 118, wherein R^(x) is selected from —CH₂R^(∘), —CH₂OR^(∘), —CH₂N(R^(∘))₂, —CH₂C(O)OR^(∘), and —CH₂C(O)N(R^(∘))₂.

Embodiment 128. The compound according to embodiment 127, wherein R^(x) is selected from —CH₂OH, —CH₂OCH₃, —CH₂CO₂CH₃, CH₂CO₂CH₂CH₃, —CH₂C(O)NH₂, —CH₂C(O)NHCH₃, and —CH₂C(O)N(CH₃)₂.

Embodiment 129. The compound according to any one of embodiments 96-107, wherein R^(x) is selected from S(O)₂N(R)₂, C(O)OR, and C(O)N(R)₂.

Embodiment 130. The compound according to embodiment 129, wherein R^(x) is S(O)₂N(R)₂.

Embodiment 131. The compound according to embodiment 130, wherein R^(x) is SO₂NH₂.

Embodiment 132. The compound according to embodiment 129, wherein R^(x) is C(O)OR.

Embodiment 133. The compound according to embodiment 132, wherein R^(x) is selected from CO₂CH₃ and CO₂CH₂CH₃.

Embodiment 134. The compound according to embodiment 129, wherein R^(x) is C(O)N(R)₂.

Embodiment 135. The compound according to embodiment 134, wherein R^(x) is selected from C(O)NH₂ and C(O)N(CH₃)₂.

Embodiment 136. The compound according to any one of embodiments 96-135, wherein R¹ is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 137. The compound according to embodiment 136, wherein R¹ is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 138. The compound according to embodiment 137, wherein R¹ is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur

Embodiment 139. The compound according to embodiment 136, wherein R¹ is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms.

Embodiment 140. The compound according to embodiment 139, wherein R¹ is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms.

Embodiment 141. The compound according to embodiment 136, wherein R¹ is selected from

Embodiment 142. The compound according to embodiment 141, wherein R¹ is selected from

Embodiment 143. The compound according to any one of embodiments 96-142, wherein L is an optionally substituted C₁₋₂ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —S(O)₂—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 144. The compound according to embodiment 143, wherein L is an optionally substituted C₁₋₂ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —S(O)₂—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 145. The compound according to embodiment 143 or 144, wherein L is an optionally substituted C₁₋₂ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(H)—, —S—, —S(O)₂—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 146. The compound according to any one of embodiments 96-142, wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —S(O)₂—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 147. The compound according to embodiment 146, wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(R)—, —S—, —S(O)₂—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 148. The compound according to embodiment 146 or 147, wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein one or two carbon atoms in the aliphatic chain are optionally replaced by a group independently selected from —O—, —N(H)—, —S—, —S(O)₂—, —C(O)—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 149. The compound according to any one of embodiments 96-142, wherein L is an optionally substituted C₁₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(R)—, —S—, —S(O)₂—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 150. The compound according to embodiment 149, wherein L is an optionally substituted C₁₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(R)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 151. The compound according to embodiment 149 or 150, wherein L is an optionally substituted C₁₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(H)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 152. The compound according to embodiment 149 or 150, wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(R)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 153. The compound according to embodiment 152, wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein one carbon atom in the aliphatic chain is replaced by —C(O)—, and one additional carbon atom is optionally replaced by a group selected from —O—, —N(H)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclic ring.

Embodiment 154. The compound according to any one of embodiments 96-142, wherein L is selected from

Embodiment 155. The compound according to any one of embodiments 96-142, wherein L is selected from

Embodiment 156. The compound according to embodiment 155, wherein L is selected from

Embodiment 157. The compound according to embodiment 155, wherein L is selected from

Embodiment 158. The compound according to any one of embodiments 96-157, wherein R is hydrogen.

Embodiment 159. The compound according to any one of embodiments 96-157, wherein R is —CH₃.

Embodiment 160. The compound according to any one of embodiments 96-157, wherein R is optionally substituted C₁₋₆ aliphatic.

Embodiment 161. The compound according to embodiment 160, wherein R is

aliphatic optionally substituted with oxo and OR^(∘).

Embodiment 162. The compound according to embodiment 161, wherein R^(∘) is C₁₋₆ aliphatic.

Embodiment 163. The compound according to embodiment 160, wherein R is methyl or ethyl.

Embodiment 164. The compound according to any one of embodiments 96-163, wherein R² is hydrogen.

Embodiment 165. The compound according to any one of embodiments 96-163, wherein R² is halogen, N(R)₂, OR, or an optionally substituted group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 166. The compound according to embodiment 165, wherein R² is N(R)₂.

Embodiment 167. The compound according to embodiment 166, wherein R is NH₂.

Embodiment 168. The compound according to embodiment 165, wherein R² is optionally substituted C₁₋₆ aliphatic.

Embodiment 169. The compound according to embodiment 168, wherein R² is selected from methyl, ethyl, t-butyl, and neopentyl.

Embodiment 170. The compound according to embodiment 165, wherein R² is optionally substituted cyclohexyl.

Embodiment 171. The compound according to embodiment 165, wherein R² is optionally substituted phenyl.

Embodiment 172. The compound according to embodiment 165, wherein R² is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 173. The compound according to embodiment 172, wherein R² is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 174. The compound according to embodiment 172 or 173, wherein R² is an optionally substituted group selected from thiophenyl, pyrazolyl, and imidazolyl.

Embodiment 175. The compound according to embodiment 172, wherein R² is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms.

Embodiment 176. The compound according to embodiment 175, wherein R² is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms.

Embodiment 177. The compound according to embodiment 176, wherein R² is an optionally substituted group selected from pyridinyl or pyrimidinyl.

Embodiment 178. The compound according to embodiment 165, wherein R² is an optionally substituted 8- to 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring.

Embodiment 179. The compound according to embodiment 178, wherein R² is an optionally substituted 9-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring.

Embodiment 180. The compound according to embodiment 179, wherein R² is optionally substituted 2,3-dihydro-1H-indenyl.

Embodiment 181. The compound according to embodiment 178, wherein R² is an optionally substituted 10-membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring.

Embodiment 182. The compound according to embodiment 181, wherein R² is optionally substituted group selected from 1,2,3,4-tetrahydronaphthalenyl or naphthalenyl.

Embodiment 183. The compound according to embodiment 165, wherein R² is an optionally substituted 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 184. The compound according to embodiment 183, wherein R² is an optionally substituted 9-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 185. The compound according to embodiment 183, wherein R² is an optionally substituted 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 186. The compound according to embodiment 185, wherein R² is

an optionally substituted group selected from chromanyl, isochromanyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, and 2H-benzo[b][1,4]oxazin-3(4H)-onyl.

Embodiment 187. The compound according to embodiment 165, wherein R² is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 188. The compound according to embodiment 187, wherein R² is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 189. The compound according to embodiment 187 or 188, wherein R² is an optionally substituted group selected from indolyl, benzopyrazolyl, benzimidazolyl, and imidazo[1,2-a]pyridinyl.

Embodiment 190. The compound according to embodiment 165, wherein R² is

selected from the group consisting of

Embodiment 191. The compound according to embodiment 165, wherein R² is

selected from the group consisting of

Embodiment 192. The compound according to embodiment 190, wherein R² is selected from

Embodiment 193. The compound according to embodiment 191, wherein R² is selected from

Embodiment 194. The compound according to embodiment 96, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 195. The compound according to embodiment 96, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 196. The compound according to embodiment 96, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 197. The compound according to embodiment 96, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 198. The compound according to embodiment 96, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

Embodiment 199. The compound according to embodiment 96, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 200. The compound according to embodiment 96, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

Embodiment 201. The compound according to embodiment 96, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

Embodiment 202. The compound according to any one of embodiments 1, 3, 4, 8, 12-89, 90a, 91, 96, 98, 99, 101, 104, 108-197, 199, and 201, wherein Ring A is

Embodiment 203. The compound according to embodiment 202, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 204. The compound according to embodiment 202, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 205. The compound according to embodiment 202, wherein the compound is

or a pharmaceutically acceptable salt thereof.

Embodiment 206. The compound according to embodiment 202, wherein the compound is

or a pharmaceutically acceptable salt thereof.

Embodiment 207. The compound according to embodiment 202, wherein the compound is

or a pharmaceutically acceptable salt thereof.

Embodiment 208. The compound according to embodiment 202, wherein the compound is

or a pharmaceutically acceptable salt thereof.

Embodiment 209. The compound according to embodiment 202, wherein the compound is

or a pharmaceutically acceptable salt thereof.

Embodiment 210. The compound according to embodiment 202, wherein the compound is

or a pharmaceutically acceptable salt thereof.

Embodiment 211. The compound according to embodiment 202, wherein the compound is

or a pharmaceutically acceptable salt thereof.

Embodiment 212. A pharmaceutical composition comprising a compound according to any one of embodiments 96-211 and a pharmaceutically acceptable carrier.

Embodiment 213. A method comprising a step of:

administering a compound according to any one of embodiments 96-211 to a subject who (i) has a condition characterized by axonal degeneration or (ii) is at risk of developing a condition characterized by axonal degeneration.

Embodiment 214. A method of treating or preventing axonal degeneration comprising administering to a subject in need thereof a compound according to any one of embodiments 96-211.

Embodiment 215. The method according to embodiment 94 or embodiment 214, wherein the axonal degeneration is associated with a neurodegenerative disease or disorder.

Embodiment 216. The method according to embodiment 215, wherein the neurodegenerative disease or disorder is selected from an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.

Embodiment 217. The method according to embodiment 215 or embodiment 216, wherein the neurodegenerative disease or disorder is selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy, and chemotherapy-induced peripheral neuropathy.

Embodiment 218. The method according to embodiment 217, wherein the neurodegenerative disease or disorder is amyotrophic lateral sclerosis (ALS).

Embodiment 219. The method according to embodiment 217, wherein the neurodegenerative disease or disorder is multiple sclerosis (MS).

Embodiment 220. The method according to embodiment 217, wherein the neurodegenerative disease or disorder is diabetic neuropathy.

Embodiment 221. The method according to embodiment 217, wherein the neurodegenerative disease or disorder is chemotherapy-induced peripheral neuropathy.

Embodiment 222. A method of inhibiting SARM1 comprising contacting a biological sample with a compound according to any one of embodiments 96-211.

Compositions

In some embodiments, a compound of Formula I or Formula I′ may be provided in a composition, e.g., in combination (e.g., admixture) with one or more other components.

In some embodiments, the present disclosure provides compositions that comprise and/or deliver a compound of Formula I or Formula I′, or an active metabolite thereof, e.g., when contacted with or otherwise administered to a system or environment e.g., which system or environment may include SARM1 NADase activity; in some embodiments, administration of such a composition to the system or environment achieves inhibition of SARM1 activity as described herein.

In some embodiments, a provided composition as described herein may be a pharmaceutical composition in that it comprises an active agent and one or more pharmaceutically acceptable excipients; in some such embodiments, a provided pharmaceutical composition comprises and/or delivers a compound of Formula I or Formula I′, or an active metabolite thereof to a relevant system or environment (e.g., to a subject in need thereof) as described herein.

In some embodiments, one or more compounds of Formula I or Formula I′ is provided and/or utilized in a pharmaceutically acceptable salt form.

Among other things, the present disclosure provides compositions comprising a compound of Formula I or Formula I′, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in provided compositions is such that is effective to measurably inhibit axonal degeneration in a biological sample or in a patient. In certain embodiments, a provided compound or composition is formulated for administration to a patient in need of such composition. The compounds and compositions, according to the methods of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or disorder described herein. Provided compounds are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the provided compounds and compositions will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will vary from subject to subject, depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed and its route of administration; the species, age, body weight, sex and diet of the patient; the general condition of the subject; the time of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and the like.

Provided compositions may be administered orally, parenterally, by inhalation or nasal spray, topically (e.g., as by powders, ointments, or drops), rectally, buccally, intravaginally, intraperitoneally, intracisternally or via an implanted reservoir, depending on the severity of the condition being treated. Preferably, the compositions are administered orally, intraperitoneally or intravenously. In certain embodiments, provided compounds are administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Sterile injectable forms of provided compositions may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a provided compound, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and/or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. The active compounds can also be in micro-encapsulated form with one or more excipients as noted above.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings (i.e. buffering agents) and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Alternatively, pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the compounds of the present disclosure with suitable non-irritating excipients or carriers that are solid at room temperature but liquid at body (e.g. rectal or vaginal) temperature and therefore will melt in the rectum or vaginal cavity to release the active compound. Such materials include cocoa butter, a suppository wax (e.g., beeswax) and polyethylene glycols.

Pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.

Dosage forms for topical or transdermal administration of a provided compound include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

Pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Most preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration.

Identification and/or Characterization of Compounds and/or Compositions

Among other things, the present disclosure provides various technologies for identification and/or characterization of compounds and/or compositions as described herein. For example, the present disclosure provides various assays for assessing SARM1 inhibitory activity, and specifically for assessing SARM1 inhibitory activity.

In some embodiments, performance of one or more compounds or compositions of interest in an assay as described herein is compared with that of an appropriate reference. For example, in some embodiments, a reference may be absence of the relevant compound or composition. Alternatively or additionally, in some embodiments, a reference may be presence of an alternative compound or composition, e.g., which alternative compound or composition has known performance (e.g., as a positive control or a negative control, as is understood in the art) in the relevant assay. In some embodiments, a reference may be an alternative but comparable set of conditions (e.g., temperature, pH, salt concentration, etc.). In some embodiments, a reference may be performance of the compound or composition with respect to a SARM1 variant.

Still further alternatively or additionally, in some embodiments, performance of one or more compounds or compositions of interest in an assay as described herein may be assessed in the presence of an appropriate reference compound or composition, for example, so that ability of the compound or composition to compete with the reference is determined.

In some embodiments, a plurality of compounds or compositions of interest may be subjected to analysis in a particular assay and/or compared with the same reference. In some embodiments, such a plurality of compounds or compositions may be or include a set of compounds or compositions that is considered to be a “library” because multiple members share one or more features (e.g., structural elements, source identity, synthetic similarities, etc.).

Certain exemplary assays that may be useful in the practice of the present disclosure are exemplified in the Examples below. Those skilled in the art, reading the present disclosure, will be aware that useful or relevant systems for identifying and/or characterizing compounds and/or compositions in accordance with the present disclosure are not limited to those included in the Examples, or otherwise discussed below.

In some embodiments, compounds and/or compositions may be identified based on and/or characterized by one or more activities or characteristics such as, for example: promoting axonal integrity, cytoskeletal stability, and/or neuronal survival. In some embodiments, provided SARM1 inhibitors inhibit catabolism of NAD+ to by SARM1. In some embodiments, provided SARM1 inhibitors slow the rate of NAD+ catabolism.

In some embodiments, provided SARM1 inhibitors reduce or inhibit binding of NAD+ by SARM1. In some embodiments, provided SARM1 inhibitors bind to SARM1 within a pocket comprising one or more catalytic residues (e.g., a catalytic cleft of SARM1). Examples of such catalytic residues include the glutamic acid at position 642 (E642).

In some embodiments, provided SARM1 inhibitors disrupt and/or prevent multimerization of the TIR1 domain of SARM1. In some embodiments, provided SARM1 inhibitors disrupt the multimerization of the SAM domains. In some embodiments, provided SARM1 inhibitors disrupt the axonal signaling cascade that leads to depletion of NAD+.

In some embodiments, the present disclosure provides assays useful for identifying and/or characterizing one or more activities and/or characteristics of compound and/or compositions of interest. For example, in some embodiments, the present disclosure provides in vitro, cellular, and/or in vivo systems for assessing one or more such activities and/or characteristics.

SARM1 Activity Assays

In some embodiments, a method of identifying a SARM1 inhibitor comprises: a) providing a mixture comprising i) a mutant or fragment of SARM1, ii) NAD+ and iii) a candidate inhibitor, wherein the mutant or fragment has constitutive activity; b) incubating the mixture; c) quantifying NAD+ in the mixture after the incubating; and d) identifying the candidate inhibitor compound as an inhibitor if the amount of NAD+ is greater than that of a control mixture that does not contain the candidate inhibitor.

In some embodiments, provided are methods of identifying a SARM1 inhibitor, comprising: a) providing a mixture comprising i) a full-length SARM1, ii) NAD+ and iii) a candidate inhibitor, wherein the full-length SARM1 has constitutive activity; b) incubating the mixture; c) quantifying NAD+ and ADPR (or cADPR) in the mixture after the incubating; d) determining the molar ratio of NAD+: ADPR (or cADPR); and e) identifying the candidate inhibitor compound as an inhibitor if the molar ratio is greater than that of a control mixture that does not contain the candidate inhibitor.

In some embodiments, provided are methods of identifying a SARM1 inhibitor, comprising: a) providing a mixture comprising a solid support to which is bound i) a full-length SARM1 and at least one tag, ii) NAD+, and iii) a candidate inhibitor; b) incubating the mixture; c) quantifying the NAD+ after the incubating; and d) identifying the candidate inhibitor compound as a SARM1 inhibitor if the concentration of NAD+ is greater than that of a control.

SARM1 Binding Assays

In some embodiments, the efficacy of provided SARM1 inhibitors can be determined according to, e.g., the assays described in WO 2018/057989, published on Mar. 29, 2018, which is hereby incorporated by reference in its entirety. In some embodiments, the provided SARM1 inhibitors can be applied to a solution containing SARM1 or a fragment thereof. In some embodiments, the provided SARM1 inhibitors can be applied to an in vitro system. In some embodiments, the provided SARM1 inhibitors can be applied to an in vivo. In some embodiments, the provided SARM1 inhibitors can be applied to a patient. In some embodiments, a SARM1 inhibitor can be mixed with SARM1 or fragment thereof that has been labeled with an epitope tag. In some embodiments, the amount of bound SARM1 inhibitor can be compared to the amount of unbound SARM1 inhibitor, yielding the affinity for the SARM1 inhibitor.

In some embodiments, the mutant or fragment of SARM1 is a SAM-TIR fragment having constitutive activity. Fragments of SARM1 having constitutive activity include, for example and without limitation, a SARM1 with the autoinhibitory domain deleted; at least one point mutation of SARM1 that renders the autoinhibitory domain inactive; a fragment of SARM1 containing a TIR domain; or a fragment of SARM1 consisting of SAM and TIR domains. In some embodiments a SARM1 polypeptide can include one or more additional amino acid sequences that can act as tags, such as a His tag, a streptavidin tag, or a combination thereof. In some embodiments a SARM1 polypeptide can include a tag at the amino terminus, at the carboxy terminus, or a combination thereof. In some embodiments, SARM1 or fragment thereof labeled with an epitope tag can be used to measure the binding efficacy of provided SARM1 inhibitors.

Purification of SARM1-TIR domains

In some embodiments, a SARM1-TIR domain can be engineered with various protein, or epitope, tags that can be useful, for example, in purification. In some embodiments, the present disclosure also provides for a NRK1-HEK293T cell line comprising HEK293T cells transformed with a Nicotinamide Riboside Kinase 1 (NRK1). In some embodiments, HEK293T cells transformed or transfected with a DNA sequence encoding Nicotinamide Riboside Kinase 1 (NRK1). In some embodiments, the DNA encoding NRK1 can be genomic or cDNA. In some embodiments, HEK293T cells are stably or transiently transfected with DNA encoding NRK1 from a source exogenous to the host cell. In some embodiments, HEK293T cells are stably or transiently transfected with DNA encoding NRK1 such that the cells express NRK1 at an elevated level compared to control cells. In some embodiments, DNA encoding NRK1 is under the control of one or more exogenous regulatory DNA sequences such as a promoter, an enhancer or a combination thereof. In some embodiments, a combination of a DNA sequences encoding NRK1 and regulatory sequences is a non-naturally occurring combination. In some embodiments, DNA encoding NRK1, either genomic or cDNA, comprises an expression vector such as an FCIV expression vector. In some embodiments, DNA encoding NRK1 is derived from genomic DNA or cDNA from a vertebrate or invertebrate species such as, but not limited to, human, mouse, zebrafish or a Drosophila. In some configurations, the NRK1 DNA is a human NRK1 DNA.

Applications and Uses

The present disclosure provides a variety of uses and applications for compounds and/or compositions as described herein, for example in light of their activities and/or characteristics as described herein. In some embodiments, such uses may include therapeutic and/or diagnostic uses. Alternatively, in some embodiments such uses may include research, production, and/or other technological uses.

In one aspect, the present disclosure provides methods comprising administering one or more compounds of Formula I or Formula I′ to a subject, e.g., to treat, prevent, or reduce the risk of developing one or more conditions characterized by axonal degeneration. In some such embodiments, the compound of Formula I or Formula I′ is a SARM1 inhibitor.

Another embodiment of the present disclosure relates to a method of inhibiting SARM1 activity in a patient comprising steps of administering to said patient a provided compound, or a composition comprising said compound.

Inhibition of enzymes in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to biological assays, gene expression studies, and biological target identification.

In certain embodiments, the present disclosure relates to a method of treating axonal degeneration in a biological sample comprising the step of contacting said biological sample with a compound or composition of Formula I or Formula I′. In some embodiments, one or more compounds and/or compositions as described herein are useful, for example as a method of for inhibiting the degradation of neurons derived from a subject. In some embodiments, one or more compounds and/or compositions as described herein, are useful for inhibiting the degeneration of a neuron, or portion thereof, cultured in vitro. In some embodiments, one or more compounds and/or compositions as described herein, are useful as stabilizing agents to promote in vitro neuronal survival.

In some embodiments, provided compounds and/or compositions inhibit NADase activity of SARM1. Alternatively or additionally, in some embodiments, provided compounds alleviate one or more attributes of neurodegeneration. In some embodiments, the present disclosure provides methods of treating a neurodegenerative disease or disorder associated with axonal degeneration.

In some embodiments, one or more compounds and/or compositions as described herein are useful, for example, in the practice of medicine. In some embodiments, one or more compounds and/or compositions as described herein are useful, for example, to treat, prevent, or ameliorate axonal degeneration (e.g., one or more features or characteristics thereof). In some embodiments, one or more compounds and/or compositions as described herein are useful, for example to inhibit axonal degeneration, including axonal degeneration that results from reduction or depletion of NAD+. In some embodiments, one or more compounds and/or compositions as described herein are useful, for example to prevent the axon distal to an axonal injury from degenerating.

In some embodiments, one or more compounds and/or compositions as described herein are useful, for example as a method for inhibiting the degradation of a peripheral nervous system neuron or a portion thereof. In some embodiments, one or more compounds and/or compositions as described herein are useful, for example as a method for inhibiting or preventing degeneration of a central nervous system neuron or a portion thereof. In some embodiments, one or more compounds or compositions as described herein is characterized that, when administered to a population of subjects, reduces one or more symptoms or features of neurodegeneration. For example, in some embodiments, a relevant symptom or feature may be selected from the group consisting of extent, rate, and/or timing of neuronal disruption.

In certain embodiments, the present disclosure provides compounds that are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure. Compounds provided by this disclosure are also useful for the study of SARM1 activity in biological and pathological phenomena and the comparative evaluation of new SARM1 activity inhibitors in vitro or in vivo. In certain embodiments, the present disclosure provides assays for identifying and/or characterizing compounds and/or compositions provided herein. In some embodiments, provided assays utilize particular reagents and/or systems (e.g., certain vector constructs and/or polypeptides) useful in assaying SARM1 activity. For example, in some embodiments, provided assays may utilize, for example, a SAM-TIR in which the SARM1 N-terminal auto-inhibitory domain is deleted, and/or one or more tagged versions of a TIR domain.

In some embodiments, one or more compounds and/or compositions as described herein are useful, for example as a method of for inhibiting the degradation of neurons derived from a subject. In some embodiments, one or more compounds and/or compositions as described herein, are useful for inhibiting the degeneration of a neuron, or portion thereof, cultured in vitro. In some embodiments, one or more compounds and/or compositions as described herein, are useful as stabilizing agents to promote in vitro neuronal survival.

In some embodiments, one or more compounds and/or compositions as described herein are useful, for example in affecting biomarkers associated with neurodegeneration. In some embodiments, changes in biomarkers can be detected systemically or with a sample of cerebral spinal fluid (CSF), plasma, serum, and/or tissue from a subject. In some embodiments, one or more compounds and/or compositions can be used to affect a change in the concentration of neurofilament protein light (NF-L) and/or neurofilament protein heavy (NF-H) contained the cerebral spinal fluid of a subject. In some embodiments, one or more compounds and/or compositions as described herein can affect constitutive NAD and/or cADPR levels in neurons and/or axons.

In some embodiments, one or more biomarkers of neurodegeneration comprises: concentration of neurofilament light chain protein (NF-L) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; concentration of neurofilament heavy chain protein (NF-H) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; concentration of alpha-synuclein in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, and a plasma sample from the subject; constitutive NAD+ levels in neurons and/or axons of the subject; constitutive cADPR levels in neurons and/or axons of the subject; levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject; and levels of C—C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colony stimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: a cerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample, a nerve biopsy sample, and a brain biopsy sample from the subject.

In some embodiments, one or more compounds and/or compositions as described herein can affect a detectable change in the levels of one or more neurodegeneration-associated proteins in a subject. Such proteins include, but are not limited to, albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein (GFAP), heart-type fatty acid binding protein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse (NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau, and/or total-tau. In some embodiments, one or more compounds and/or compositions as described herein can affect a change in cytokines and/or chemokines, including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1, and/or Il6.

Diseases, Disorders, and Conditions

In some embodiments, compounds and/or compositions as described herein may be administered to subjects suffering from one or more diseases, disorders, or conditions. In some embodiments, the one or more diseases, disorders, or conditions are mediated by SARM1.

In some embodiments, a neurodegenerative disease or disorder comprises an acute or chronic disease or disorder of the peripheral nervous system (PNS), an acute or chronic disease or disorder of the central nervous system (CNS), or a disease associated with neurodegeneration.

In some embodiments, a neurodegenerative disease or disorder comprises an acute disease or disorder of the PNS. In some embodiments, an acute disease or disorder of the PNS is the result of a mechanical injury, thermal injury, or injury from a chemical agent or chemotherapy. In some embodiments, a mechanical injury comprises a compression or entrapment injury or a pressure injury. In some embodiments, a compression or entrapment injury comprises carpal tunnel syndrome, direct trauma, a penetrating injury, a contusion, a fracture or a dislocated bone. In some embodiments, a pressure injury comprises pressure involving superficial nerves, pressure from a tumor or increased intraocular pressure. In some embodiments, a chemical agent or chemotherapy comprises a cytotoxic anticancer agent, thalidomide, an epothilone, a taxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drug or an auristatin. In some embodiments, an epothilone is ixabepilone. In some embodiments, a taxane is paclitaxel or docetaxel. In some embodiments, a vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine. In some embodiments, a proteasome inhibitor is bortezomib. In some embodiments, a platinum-based drug is cisplatin, oxaliplatin, or carboplatin. In some embodiments, an auristatin is conjugated monomethyl auristatin E.

In some embodiments, a neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS. In some embodiments, a chronic disease or disorder of the PNS comprises a systemic disorder, a pain disorder, or a metabolic disease or disorder.

In some embodiments, a chronic disease or disorder of the PNS comprises inherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy (HSAN), chronic inflammatory demyelinating polyneuropathy (CIDP), idiopathic neuropathies or other peripheral neuropathies.

In some embodiments, a systemic disorder comprises diabetes, uremia, AIDS, leprosy, a nutritional deficiency, atherosclerosis, an enteric neuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.

In some embodiments, a pain disorder comprises chronic pain, fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neurogenic pain, neuropathic pain, nerve inflammation, nerve damage, shingles, herniated disc, torn ligament, or diabetes.

In some embodiments, a metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.

In some embodiments, a neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS. In some embodiments, an acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.

In some embodiments, an ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.

In some embodiments, a traumatic CNS injury comprises a spinal cord injury, a TBI, a mechanical injury to the head and/or spine, a traumatic injury to the head and/or spine, blunt force trauma, closed head injury, open head injury, exposure to a concussive and/or explosive force, a penetrating injury to the CNS, increased intraocular pressure, or damage from a force which causes axons to deform, stretch, crush or sheer.

In some embodiments, a viral encephalitis comprises enterovirus encephalitis, arbovirus encephalitis, herpes simplex virus (HSV) encephalitis, West Nile virus encephalitis, La Crosse encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, or HIV encephalopathy (HIV-associated dementia).

In some embodiments, a neurodegenerative disease or disorder comprises a chronic disease or disorder of the CNS.

In some embodiments, a chronic disease or disorder of the CNS comprises Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), Huntington's disease (HD), senile dementia, Pick's disease, Gaucher's disease, Hurler syndrome, progressive multifocal leukoencephalopathy, Alexander's disease, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinal muscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, Pelizaeus Merzbacher disease, periventricular leukomalacia, a hereditary ataxia, noise-induced hearing loss, congenital hearing loss, age-related hearing loss, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, globoid cell leukodystrophy (Krabbe's disease), Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, a spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis (NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, or spinal cord injury. In some embodiments, a chronic disease or disorder of the CNS is neurotoxic hearing loss. In some such embodiments, neurotoxic hearing loss is caused by chemotherapy or an antibiotic.

In some embodiments, a chronic disease or disorder of the CNS comprises an optic nerve disorder, a traumatic CNS injury, or a metabolic disease or disorder.

In some embodiments, an optic nerve disorder comprises an acute optic neuropathy (AON), a genetic or idiopathic retinal condition, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG), autosomal dominant optic atrophy, retinal ganglion degeneration, retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis, optic nerve degeneration associated with multiple sclerosis, Kjer's optic neuropathy, an ischemic optic neuropathy, a deficiency in vitamin B12, a deficiency in folic acid (vitamin B9), isolated vitamin E deficiency syndrome, non-arteritic anterior ischemic optic neuropathy, exposure to ethambutol, or exposure to cyanide.

In some embodiments, a disease or disorder of the CNS is a tauopathy. In some such embodiments, a tauopathy occurs as a result of progressive supranuclear palsy or corticobasal degeneration.

In some embodiments, a neurodegenerative disease or disorder is caused by or results from protein misfolding.

In some embodiments, a neurodegenerative disease or disorder is a synucleinopathy such as, e.g., abnormal accumulation of aggregates of alpha-synuclein protein in neurons.

In some embodiments, a neurodegenerative disease or disorder is a multiple system atrophy.

In some embodiments, a traumatic CNS injury comprises a traumatic brain injury (TBI), a spinal cord injury, traumatic axonal injury or chronic traumatic encephalopathy (CTE).

In some embodiments, a metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders.

In some embodiments, a neurodegenerative disease or disorder comprises a disease associated with neurodegeneration. In some embodiments, a neurodegenerative disease or disorder results from blood clotting issues, inflammation, obesity, aging, stress, cancer, or diabetes.

In some embodiments, the condition is an acute peripheral neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN) is an example of an acute peripheral neuropathy. CIPN can be associated with various drugs, such as, but not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

In some embodiments, one or more compounds and/or compositions as described herein are useful, for example, to treat one or more neurodegenerative diseases, disorders or conditions selected from the group consisting of neuropathies or axonopathies. In some embodiments, one or more compounds and/or compositions as described herein are useful, for example to treat a neuropathy or axonopathy associated with axonal degeneration. In some embodiments, a neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In some embodiments, a neuropathy associated with axonal degeneration results from a de novo or somatic mutation. In some embodiments, a neuropathy associated with axonal degeneration is selected from a list contained herein. In some embodiments, a neuropathy or axonopathy is associated with axonal degeneration, including, but not limited to Parkinson's disease, non-Parkinson's disease, Alzheimer's disease, Herpes infection, diabetes, amyotrophic lateral sclerosis, a demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS.

In some embodiments, one or more compounds or compositions as described herein is characterized that, when administered to a population of subjects, reduces one or more symptoms or features of neurodegeneration. For example, in some embodiments, a relevant symptom or feature may be selected from the group consisting of extent, rate, and/or timing of neuronal disruption. In some embodiments, neuronal disruption may be or comprise axonal degradation, loss of synapses, loss of dendrites, loss of synaptic density, loss of dendritic arborization, loss of axonal branching, loss of neuronal density, loss of myelination, loss of neuronal cell bodies, loss of synaptic potentiation, loss of action-potential potentiation, loss of cytoskeletal stability, loss of axonal transport, loss of ion channel synthesis and turnover, loss of neurotransmitter synthesis, loss of neurotransmitter release and reuptake capabilities, loss of axon-potential propagation, neuronal hyperexitability, and/or neuronal hypoexcitability. In some embodiments, neuronal disruption is characterized by an inability to maintain an appropriate resting neuronal membrane potential. In some embodiments, neuronal disruption is characterized by the appearance of inclusion bodies, plaques, and/or neurofibrillary tangles. In some embodiments, neuronal disruption is characterized by the appearance of stress granules. In some embodiments, neuronal disruption is characterized by the intracellular activation of one or more members of the cysteine-aspartic protease (Caspase) family. In some embodiments, neuronal disruption is characterized by a neuron undergoing programed cell death (e.g. apoptosis, pyroptosis, ferroapoptosis, and/or necrosis) and/or inflammation.

In some embodiments, the neurodegenerative or neurological disease or disorder is associated with axonal degeneration, axonal damage, axonopathy, a demyelinating disease, a central pontine myelinolysis, a nerve injury disease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage resulting from a leukoencephalopathy or a leukodystrophy. In some embodiments, the neurodegenerative or neurological disease or disorder is selected from the group consisting of spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy (chemotherapy induced neuropathy; CIPN), neuropathy, acute ischemic optic neuropathy, vitamin Blu deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Glaucoma, Leber's hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, west Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedrich's ataxia, hereditary ataxias, noise induced hearing loss, congenital hearing loss, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathies and axonopathies, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, spinocerebellar ataxias, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, and non-alcoholic steatohepatitis (NASH).

In some embodiments, the present disclosure provides inhibitors of SARM1 activity for treatment of neurodegenerative or neurological diseases or disorders that involve axon degeneration or axonopathy. The present disclosure also provides methods of using inhibitors of SARM1 activity to treat, prevent or ameliorate axonal degeneration, axonopathies and neurodegenerative or neurological diseases or disorders that involve axonal degeneration.

In some embodiments, the present disclosure provides methods of treating neurodegenerative or neurological diseases or disorders related to axonal degeneration, axonal damage, axonopathies, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage resulting from a leukoencephalopathy or a leukodystrophy.

In some embodiments, neuropathies and axonopathies include any disease or condition involving neurons and/or supporting cells, such as for example, glia, muscle cells or fibroblasts, and, in particular, those diseases or conditions involving axonal damage. Axonal damage can be caused by traumatic injury or by non-mechanical injury due to diseases, conditions, or exposure to toxic molecules or drugs. The result of such damage can be degeneration or dysfunction of the axon and loss of functional neuronal activity. Disease and conditions producing or associated with such axonal damage are among a large number of neuropathic diseases and conditions. Such neuropathies can include peripheral neuropathies, central neuropathies, and combinations thereof. Furthermore, peripheral neuropathic manifestations can be produced by diseases focused primarily in the central nervous systems and central nervous system manifestations can be produced by essentially peripheral or systemic diseases.

In some embodiments, a peripheral neuropathy can involve damage to the peripheral nerves, and/or can be caused by diseases of the nerves or as the result of systemic illnesses. Some such diseases can include diabetes, uremia, infectious diseases such as AIDs or leprosy, nutritional deficiencies, vascular or collagen disorders such as atherosclerosis, and autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa. In some embodiments, peripheral nerve degeneration results from traumatic (mechanical) damage to nerves as well as chemical or thermal damage to nerves. Such conditions that injure peripheral nerves include compression or entrapment injuries such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fracture or dislocated bones; pressure involving superficial nerves (ulna, radial, or peroneal) which can result from prolonged use of crutches or staying in one position for too long, or from a tumor; intraneural hemorrhage; ischemia; exposure to cold or radiation or certain medicines or toxic substances such as herbicides or pesticides. In particular, the nerve damage can result from chemical injury due to a cytotoxic anticancer agent such as, for example, taxol, cisplatinin, a proteasome inhibitor, or a vinca alkaloid such as vincristine. Typical symptoms of such peripheral neuropathies include weakness, numbness, paresthesia (abnormal sensations such as burning, tickling, pricking or tingling) and pain in the arms, hands, legs and/or feet. In some embodiments, a neuropathy is associated with mitochondrial dysfunction. Such neuropathies can exhibit decreased energy levels, i.e., decreased levels of NAD and ATP.

In some embodiments, peripheral neuropathy is a metabolic and endocrine neuropathy which includes a wide spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin. These diseases include, for example, diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamin deficiencies, and mitochondrial disorders, among others. The common hallmark of these diseases is involvement of peripheral nerves by alteration of the structure or function of myelin and axons due to metabolic pathway dysregulation.

In some embodiments, neuropathies include optic neuropathies such as glaucoma; retinal ganglion degeneration such as those associated with retinitis pigmentosa and outer retinal neuropathies; optic nerve neuritis and/or degeneration including that associated with multiple sclerosis; traumatic injury to the optic nerve which can include, for example, injury during tumor removal; hereditary optic neuropathies such as Kjer's disease and Leber's hereditary optic neuropathy; ischemic optic neuropathies, such as those secondary to giant cell arteritis; metabolic optic neuropathies such as neurodegenerative diseases including Leber's neuropathy mentioned earlier, nutritional deficiencies such as deficiencies in vitamins B12 or folic acid, and toxicities such as due to ethambutol or cyanide; neuropathies caused by adverse drug reactions and neuropathies caused by vitamin deficiency. Ischemic optic neuropathies also include non-arteritic anterior ischemic optic neuropathy. In some embodiments, the optic neuropathy is age-related macular degeneration.

In some embodiments neurodegenerative diseases that are associated with neuropathy or axonopathy in the central nervous system include a variety of diseases. Such diseases include those involving progressive dementia such as, for example, Alzheimer's disease, senile dementia, Pick's disease, and Huntington's disease; central nervous system diseases affecting muscle function such as, for example, Parkinson's disease, motor neuron diseases and progressive ataxias such as amyotrophic lateral sclerosis; demyelinating diseases such as, for example multiple sclerosis; viral encephalitides such as, for example, those caused by enteroviruses, arboviruses, and herpes simplex virus; and prion diseases. Mechanical injuries such as glaucoma or traumatic injuries to the head and spine can also cause nerve injury and degeneration in the brain and spinal cord. In addition, ischemia and stroke as well as conditions such as nutritional deficiency and chemical toxicity such as with chemotherapeutic agents can cause central nervous system neuropathies.

In some embodiments, the present disclosure provides a method of treating a neuropathy or axonopathy associated with axonal degeneration. In some such embodiments, a neuropathy or axonopathy associated with axonal degeneration can be any of a number of neuropathies or axonopathies such as, for example, those that are hereditary or congenital or associated with Parkinson's disease, Alzheimer's disease, Herpes infection, diabetes, amyotrophic lateral sclerosis, a demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS. In addition, neurodegenerative diseases not mentioned above as well as a subset of the above mentioned diseases can also be treated with the methods of the present disclosure. Such subsets of diseases can include Parkinson's disease or non-Parkinson's diseases, or Alzheimer's disease.

Subjects

In some embodiments, compounds and/or compositions as described herein are administered to subjects suffering from or susceptible to a disease, disorder or condition as described herein; in some embodiments, such a disease, disorder or condition is characterized by axonal degeneration, such as one of the conditions mentioned herein.

In some embodiments, a subject to whom a compound or composition is administered as described herein exhibits one or more signs or symptoms associated with axonal degeneration; in some embodiments, the subject does not exhibit any signs or symptoms of neurodegeneration.

In some embodiments, provided methods comprise administering a compound of Formula I or Formula I′ to a patient in need thereof. In some such embodiments, the patient is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the patient has a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.

In some embodiments, provided methods comprise administering a composition as described herein to a patient population of in need thereof. In some embodiments, the population is drawn from individuals who engage in activities where the potential for traumatic neuronal injury is high. In some embodiments, the population is drawn from athletes who engage in contact sports or other high-risk activities.

In some embodiments, the subject is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the subject is identified as being at risk of axonal degeneration, e.g., based on the subject's genotype, a diagnosis of a condition associated with axonal degeneration, and/or exposure to an agent and/or a condition that induces axonal degeneration.

In some embodiments, the patient is at risk of developing a neurodegenerative disorder. In some embodiments the patient is elderly. In some embodiments, the patient is known to have a genetic risk factor for neurodegeneration. In some embodiments, the patient has a family history of neurodegenerative disease. In some embodiments, the patient expresses one or more copies of a known genetic risk factor for neurodegeneration. In some embodiments, the patient is drawn from a population with a high incidence of neurodegeneration. In some embodiments, the patient has a hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In some embodiments, the patient has one or more copies of the ApoE4 allele.

In some embodiments, subjects to which a compound or composition as described herein is administered may be or comprise subjects suffering from or susceptible to a neurodegenerative disease, disorder or condition. In some embodiments, a neurodegenerative disease, disorder or condition may be or comprise a traumatic neuronal injury. In some embodiments, a traumatic neuronal injury is blunt force trauma, a closed-head injury, an open head injury, exposure to a concussive and/or explosive force, a penetrating injury in to the brain cavity or innervated region of the body. In some embodiments, a traumatic neuronal injury is a force which causes the axons to deform, stretch, crush or sheer.

In some embodiments, the subject engages in an activity identified as a risk factor for neuronal degradation, e.g., a subject that engages in contact sports or occupations with a high chance for traumatic neuronal injury.

For example, the subject may be a patient who is receiving, or is prescribed, a chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, but not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

In some embodiments, provided methods comprise administering a composition as described herein to a patient or patient population based on the presence or absence of one or more biomarkers. In some embodiments, provided methods further comprise monitoring the level of a biomarker in a patient or patient population and adjusting the dosing regimen accordingly.

Dosing

Those of skill in the art will appreciate that, in some embodiments, the exact amount of a particular compound included in and/or delivered by administration of a pharmaceutical composition or regimen as described herein may be selected by a medical practitioner and may be different for different subjects, for example, upon consideration of one or more of species, age, and general condition of the subject, and/or identity of the particular compound or composition, its mode of administration, and the like. Alternatively, in some embodiments, the amount of a particular compound included in and/or delivered by administration of a pharmaceutical composition or regimen as described herein may be standardized across a relevant patient population (e.g., all patients, all patients of a particular age or stage of disease or expressing a particular biomarker, etc.).

A provided compound or composition of the present disclosure is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of a provided compound or composition of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the clinical condition of the individual patient; the cause of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, delivery site of the agent, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit SARM1 activity as required to prevent or treat the undesired disease or disorder, such as for example, neurodegeneration or traumatic neural injury.

A pharmaceutically acceptable composition of this disclosure can be administered to humans and other animals orally, rectally, intravenously, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease, disorder or infection being treated. The daily dose is, in certain embodiments, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. This dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

In some embodiments, compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intradermal, intraocular, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

In some embodiments, pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Most preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.

Those additional agents may be administered separately from a provided compound or composition thereof, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a provided compound in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another, normally within five hours from one another.

It should also be understood that a specific dosage and treatment regimen for any particular patient may depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. In some embodiments, the amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.

In some embodiments, SARM1 inhibition as described herein may be utilized in combination with one or more other therapies to treat a relevant disease, disorder, or condition. In some embodiments, dosing of a SARM1 inhibitor is altered when utilized in combination therapy as compared with when administered as monotherapy; alternatively or additionally, in some embodiments, a therapy that is administered in combination with SARM1 inhibition as described herein is administered according to a regimen or protocol that differs from its regimen or protocol when administered alone or in combination with one or more therapies other than SARM1 inhibition. In some embodiments, compositions which comprise an additional therapeutic agent, that additional therapeutic agent and a provided compound may act synergistically. In some embodiments, one or both therapies utilized in a combination regimen is administered at a lower level or less frequently than when it is utilized as monotherapy.

In some embodiments, compounds and/or compositions described herein are administered with a chemotherapeutic agent including, but not limited to, alkylating agents, anthracyclines, taxanes, epothilones, histone deacetylase inhibitors, topoisomerase inhibitors, kinase inhibitors, nucleotide analogs, peptide antibiotics, platinum-based agents, retinoids, vinca alkaloids and derivatives. In some embodiments, compounds and/or compositions described herein are administered in combination with PARP inhibitors.

EXEMPLIFICATION

The present teachings including descriptions provided in the Examples that are not intended to limit the scope of any claim. Unless specifically presented in the past tense, inclusion in the Examples is not intended to imply that the experiments were actually performed. The following non-limiting examples are provided to further illustrate the present teachings. Those of skill in the art, in light of the present disclosure, will appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present teachings.

Methods

Some methods and compositions described herein utilize laboratory techniques well known to skilled artisans, and can be found in laboratory manuals such as Sambrook, J., et al., Molecular Cloning: A Laboratory Manual, 3rd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 2001; Methods In Molecular Biology, ed. Richard, Humana Press, N J, 1995; Spector, D. L. et al., Cells: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1998; and Harlow, E., Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1999. Methods of administration of pharmaceuticals and dosage regimes, can be determined according to standard principles of pharmacology, using methods provided by standard reference texts such as Remington: the Science and Practice of Pharmacy (Alfonso R. Gennaro ed. 19th ed. 1995); Hardman, J. G., et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, 1996; and Rowe, R. C., et al., Handbook of Pharmaceutical Excipients, Fourth Edition, Pharmaceutical Press, 2003.

Example 1: Synthesis of Compounds General Synthetic Methods

The compounds according to the present invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably, the compounds are obtained in analogous fashion to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section. In some cases, the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used.

The general processes for preparing the compounds according to the invention will become apparent to the one skilled in the art studying the following schemes. Starting materials may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the one skilled in the art.

Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Intermediates and products may be purified by chromatography on silica gel, recrystallization and/or reverse phase HPLC (RHPLC). Discrete enantiomers may be obtained by resolution of racemic products using chiral HPLC. RHPLC purification methods used anywhere from 0-100% acetonitrile in water containing 0.1% formic acid, 0.1-0.01% TFA, 10 mM aqueous ammonium bicarbonate or 0.2% aqueous ammonium hydroxide and used one of the following columns:

a) Waters Xbridge C18 10 μm 30×100 mm column

b) Waters Sunfire C18 10 μm 30×100 mm column

c) Waters Xbridge C18 3.5 μm 50×4.6 mm column

d) HALO C18 2.7 μm 30×4.6 mm column

e) Waters Sunfire C18 3.5 μm 50×4.6 mm column

SYNTHETIC EXAMPLES

Carboxylic acids used to prepare compounds disclosed herein are either commercially available, can be readily prepared via one skilled in the art, or can be prepared using one of the methods below. Acid chlorides used to prepare compounds disclosed herein can be readily prepared via one skilled in the art from carboxylic acids by reagents such as oxalyl chloride and sulphonyl chloride.

Method A

To a solution of R-1 (0.97 g, 5.39 mmol) and malonic acid (0.81 mL, 8.08 mmol) in pyridine (3.15 mL) was added piperidine (53 uL, 0.539 mmol). The reaction mixture was stirred at 115° C. for 19 h. After this time, the reaction mixture was concentrated under vacuum. The residue was acidified to pH=4 with 1 M aqueous HCl and the resultant solid filtered under vacuum then triturated from acetonitrile/water to afford a solid (1.2 g) that was dissolved in methanol (19.7 mL) and dichloronickel hexahydrate (291 mg, 1.21 mmol) was added. The reaction mixture was cooled to 0° C. and sodium borohydride (307 mg, 8.10 mmol) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. The reaction mixture was acidified with 2M aqueous HCl (10 mL) and extracted with (3:1) CHCl₃: IPA (3×20 mL). The organic phase was dried (Na₂SO₄) and concentrated under vacuum to afford R-2 (0.59 g, 44%).

Method B

To a solution of ethyl (diethoxyphosphoryl)acetate (0.60 mL, 3.01 mmol) in THE (13 mL) cooled to 0° C. was added sodium hydride (60% in oil, 115 mg, 2.88 mmol) in one portion. The mixture was stirred at 0° C. for 20 min. A solution of R-3 (500 mg, 2.74 mmol) in THE (3 mL) was added over 2 min and the mixture was stirred at 0° C. for 1 hour then at room temperature for 24 hours. The reaction was poured onto saturated aqueous sodium bicarbonate (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine (20 mL), dried (MgSO₄), filtered and concentrated under vacuum. The residue was purified by flash column chromatography (SiO₂, 7% to 40% EtOAc in heptane) to afford R-4 as a 2:1 mixture of regioisomers (120 mg, 15%).

To a solution of R-4 (85 mg, 0.334 mmol) in methanol (3 mL) at room temperature was added dichloronickel hexahydrate (24 mg, 0.01 mmol) followed by sodium borohydride (25 mg, 0.66 mmol). The mixture was stirred at room temperature for 3 hours then treated with water (5 mL) and poured into saturated aqueous sodium bicarbonate (10 mL). The aqueous phase was extracted with EtOAc (3×20 mL), washed with brine (20 mL), dried (MgSO₄), filtered and concentrated under vacuum. The crude material was purified by via flash column chromatography (SiO₂, 2% to 30% EtOAc in heptane) to afford ethyl 2-(7-chloro-3,4-dihydro-2H-1-benzopyran-4-yl)acetate (60 mg, 47%).

To a solution of ethyl 2-(7-chloro-3,4-dihydro-2H-1-benzopyran-4-yl)acetate (60 mg, 0.22 mmol) in THE (2 mL) and water (0.2 mL) was added lithium hydroxide hydrate (19 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 20 h then quenched by addition of 1M aqueous HCl (10 mL). The aqueous layer was extracted with EtOAc (3×8 mL), combined organic extracts dried (MgSO₄), filtered and concentrated under vacuum to afford R-5 (50 mg, 94%).

Method C

To a solution of 3-ethoxy-3-oxopropanoic acid (0.63 mL, 5.30 mmol) in pyridine (2 mL) was added piperidine (35 uL, 0.35 mmol) and R-6 (500 mg, 3.53 mmol). The reaction mixture was stirred at 115° C. for 2 hours. After this time, the reaction mixture was cooled then neutralised with 2M aqueous HCl. The aqueous mixture was extracted with EtOAc (3×20 mL), organic phase dried (Na₂SO₄) and concentrated under vacuum. The crude was purified by flash column chromatography using a gradient from (SiO₂, 0% to 50% EtOAc in heptane) to afford the ethyl ester (448 mg, 50%).

To a solution of the ethyl ester (400 mg, 1.89 mmol) in methanol (3.3 mL) was added dichloronickel hexahydrate (227 mg, 0.95 mmol). The reaction mixture was cooled to 0° C. and sodium borohydride (143 mg, 3.78 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with EtOAc (20 mL) and filtered through glass fibre filter paper. The filtrate was washed with saturated aqueous sodium bicarbonate (2×10 mL), brine (10 mL), dried (Na₂SO₄) and concentrated under vacuum to afford the saturated ethyl ester (212 mg, 52%).

To a solution of the saturated ethyl ester (212 mg, 0.84 mmol) in THE (1 mL) and methanol (1 mL) was added 2M aqueous LiOH (0.42 mL, 0.84 mmol). The reaction mixture was stirred at room temperature for 3 hours then volatiles were concentrated under vacuum. The remaining aqueous mixture was acidified to pH 3 with 2M aqueous HCl then extracted with (3:1) DCM: MeOH (3×10 mL), dried (Na₂SO₄) and concentrated under vacuum to afford R-7 (93 mg, 56%).

Synthesis of Amines

Amines used to prepare final compounds of the invention are either commercially available, can be readily prepared via one skilled in the art, or can be prepared using one of the methods below.

Method D

The mixture of R-8 (500 mg, 3.88 mmol) and aminoguanidine hydrochloride (853 mg, 7.76 mmol) was stirred at 190° C. for 2 h. The reaction mixture was cooled to room temperature, and then water (5 mL) was added, and neutralized with aqueous NaOH solution (6 mol/L). The mixture was filtered, and the filtrate was purified by Prep-HPLC to obtain R-9 (60 mg, 10%).

Method E

The solution of methyl isonicotinate (4 g, 29 mmol) in anhydrous THE (40 mL) was cooled to −60° C. in a dry ice/ethanol bath with N₂ protection. LHMDS (1.0 M, 43.6 ml) was added dropwise while the temperature was kept below −55° C. After stirring at −60° C. for 1.5 hours, propionitrile (3 mL, 43.6 mmol) was added slowly. The reaction mixture was stirred for another 1.5 hours at −60° C., and then allowed to warm to room temperature. The THF was removed under reduced pressure, and the residue was treated with CH₂Cl₂ (50 mL) and resultant solid was filtered, washed with cold CH₂Cl₂ (50 mL) and dried to give the lithium salt intermediate (5 g).

The lithium salt (1 g, 6.25 mmol) in ethanol (100 ml) was slowly treated with AcOH (375 mg, 6.25 mmol), followed by hydrazine hydrate (98 wt %, 1.17 g, 18.75 mmol). The reaction mixture was stirred at reflux overnight. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 8% MeOH in CH₂Cl₂) to give R-11 (672 mg).

Synthesis of Exemplary Compounds

Method F: Synthesis of Example 17

R-13 (0.30 g, 1.87 mmol) and R-12 (22 uL, 1.87 mmol) were dissolved in DMF (2.0 mL) and N-ethyl-N-isopropyl-propan-2-amine (654 uL, 3.75 mmol) and propanephosphonic acid anhydride (50% in ethyl acetate, 1.67 mL, 2.81 mmol) were added. The reaction mixture was stirred at 100° C. for 24 h. After this time, the reaction mixture was diluted with ethyl acetate and the organics washed with saturated aqueous sodium bicarbonate, dried (MgSO₄) and concentrated under vacuum. The crude product was recrystallized from methanol affording the title compound (323 mg, 52%).

The following compounds were prepared in similar fashion from the appropriate carboxylic acids and amines: Examples 1, 12-13, 15-17, 20-23, 29, 37-39, 44-46, 48-50, 52-55, 57-58, 61, 64-66, 70, 76-81, 83-87, 97, 101-108, 116-120, 158, 159, 161, 162, 167-173, 177-182, 186-197, 202-215, 220-222, 224, 227-237, 263-266, 270-273, 278-280, 282-285, 295, 297, 301-306, 309-312, 316, 319, and 321-323.

Method G: Synthesis of Example 146

To a mixture of R-14 (150 mg, 0.93 mmol) and DIPEA (488 μL, 2.79 mmol) in CH₂Cl₂ (2.5 mL) was added R-13 (138 μL, 0.93 mmol) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with CH₂ Cl₂, filtered and the solid was washed with CH₂ Cl₂. The solid residue was subsequently heated to 250° C. for 30 min. The crude product was purified by preparative HPLC to afford the title compound (72 mg, 26%).

The following compounds were prepared in similar fashion from the appropriate carboxylic acids and amines: Examples 113, 121-123, 127-128, 133, and 143-145.

Method H: Synthesis of Example 27

To a solution of R-15 (160 mg, 0.86 mmol), R-11 (150 mg, 0.86 mmol), DIPEA (0.30 mL, 1.72 mmol) in anhydrous DMF (3 mL) was added propanephosphonic acid anhydride (50% in ethyl acetate, 0.77 mL, 1.29 mmol). The mixture was purged with nitrogen and stirred in a sealed vial at room temperature for 1 hour. After this time, saturated aqueous sodium bicarbonate (10 mL) and water (10 mL) were added. The mixture was extracted with DCM (3×10 mL) and the combined organic layers were dried (MgSO₄), filtered and concentrated under vacuum. The crude product was purified by flash column chromatography (SiO₂, 0-10% MeOH in CH₂ Cl₂) to give a solid that was triturated in CH₂Cl₂ (5 mL), collected under vacuum filtration, washed with CH₂C₂(3×10 mL) and dried in a vacuum oven at 40° C. for 7 days to afford the title compound (115 mg, 38%).

The following compounds were prepared in similar fashion from the appropriate carboxylic acids and amines: Examples 2, 5, 8-11, 14, 18, 34-36, 51, 59-60, 148, 150-155, 199, 200, 219, 250, 261, 262, 267, 268, 269, 274, and 291-293.

Method I: Synthesis of Example 75

To a mixture of R-16 (402 mg, 1.86 mmol) and N-ethyl-N-isopropyl-propan-2-amine (683 μL, 3.91 mmol) in DCM (2 mL) at 0° C. was added oxalyl chloride (182 μL, 2.05 mmol) followed by R-17 (300 mg, 1.86 mmol). The reaction mixture was stirred at room temperature for 1 hour then stood at room temperature for 48 hours. The reaction mixture was diluted with DCM and water, filtered and solid washed with further DCM to give a solid (324 mg), which was subsequently heated to 250° C. for 5 min in a sealed vial. The crude residue was purified by flash column chromatography (SiO₂, 0% to 100% ethyl acetate in heptane then 0% to 20% MeOH in DCM) to afford crude product that was further purified by trituration with methanol and then DCM to afford the title compound (9 mg, 2%).

The following compounds were prepared in similar fashion from the appropriate carboxylic acids and amines: Examples 73-75, 93-96, 109, 124-126, 129-132, and 134-142.

Method J: Synthesis of Example 114

To a mixture of R-17 (29 μL, 0.54 mmol), R-13 (100 mg, 0.542 mmol) and N-ethyl-N-isopropyl-propan-2-amine (279 μL, 1.60 mmol) in anhydrous DMF (1 mL) was added HATU (304 mg, 0.80 mmol) and the reaction mixture was stirred at room temperature in a sealed vial for 3 hours. The reaction mixture was washed with DCM and brine, separated through a hydrophobic frit and the retained aqueous layer was washed with DCM and separated. The combined organics were concentrated under vacuum and purified by preparative HPLC to afford a solid. The resulting solid was heated in a sealed tube at 250° C. for 15 min. The reaction mixture was allowed to cool to room temperature and the solid was triturated with acetonitrile and filtered under vacuum filtered to afford the title compound (25 mg, 14%).

Method K: Synthesis of Example 62

To a solution of R-17 (73 mg, 0.46 mmol) and R-18 (100 mg, 0.46 mmol) in pyridine (3.2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (71 mg, 0.46 mmol) and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was diluted with DCM and washed with brine, separated through a hydrophobic frit and the retained aqueous was washed with DCM and separated. The combined organics were concentrated under vacuum and purified by preparative HPLC to afford the title compound (3 mg, 2%).

The following compound was prepared in similar fashion from the appropriate carboxylic acid and amine: Example 47.

Method L: Synthesis of Example 30

R-18 (22 μL, 3.71 mmol), R-19 (601 mg, 3.71 mmol) and N-ethyl-N-isopropyl-propan-2-amine (1.3 mL, 7.43 mmol) were dissolved in DMF (6.0 mL) and propanephosphonic acid anhydride (50%, 3.32 mL, 5.57 mmol) was added. The reaction mixture was stirred at 100° C. for 18 h in a sealed vial. The reaction mixture was diluted with EtOAc (100 mL), washed with sat. sodium bicarbonate aq. (3×100 mL), brine (50 mL), dried (Na₂SO₄) and concentrated under vacuum. The crude product was purified by flash column chromatography using a gradient from 0% to 100% EtOAc in heptane to afford R-20 (580 mg, 38%) [LCMS Method G, ret time=0.84 min, mol ion=362.1, 364.1].

To a suspension of R-20 (930 mg, 2.57 mmol) in chloroform (10 mL) was added 4-methylbenzenesulfonic acid hydrate (1:1) (49 mg, 0.26 mmol) and 3,4-dihydro-2H-pyran (0.23 mL, 2.57 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum and the crude residue was purified by flash column chromatography (SiO₂, 0 to 100% EtOAc in heptane) afford a mixture (3:1) of R-21 and R-22 (750 mg, 63%) [LCMS Method G, ret time=1.00, mol ion=446.1, 448.1].

To a mixture of R-21 and R-22 (750 mg, 1.68 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (364 mg, 1.76 mmol) in 1,4-dioxane (5.2 mL) and 2M aqueous potassium carbonate (2.6 mL, 5.20 mmol) was added cyclopentyl(diphenyl) phosphane;dichloropalladium;iron (146 mg, 0.20 mmol). The reaction mixture was degassed for 5 min then stirred in a sealed vial at 100° C. for 2 hours. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (30 mL) and the layers were separated. The organic phase was dried (Na₂SO₄) and concentrated under vacuum. The crude residue was purified by flash column chromatography (SiO₂, 0% to 100% EtOAc in heptane then 0% to 20% methanol in EtOAc) to afford a mixture of isomers (510 mg, 68%). The isomers were dissolved in MeOH (5 mL) and treated with 4 M HCl in dioxane (5.0 mL, 20.0 mmol) and allowed to stand at room temperature for 20 min. The reaction mixture was concentrated under vacuum, then triturated with water, filtered under vacuum, washed with acetonitrile and dried in the vacuum oven for 18 hours to afford the title compound (320 mg, 77%).

The following compounds were prepared in similar fashion from the appropriate carboxylic acids and boronic esters or acids: Examples 19, 24-26, 31, 40, 163, 198, 225, 238, 239, 260, 281, 286, 294, 298, 299, 300, 307, 308, 313, 314, 315, 318, 320, 324, and 325.

Method M: Synthesis of Example 32

To a suspension of R-23 (20.0 g, 88.2 mmol) in THE (200 mL) at 0° C. was added sodium hydride (60% in oil, 3.53 g, 88.2 mmol) portionwise and the reaction mixture was stirred at room temperature under nitrogen for 30 min. The reaction mixture was cooled to 0° C., [2-(chloromethoxy)ethyl](trimethyl)silane (17 mL, 97.0 mmol) was added and the reaction mixture was stirred under nitrogen for 18 h. The reaction was quenched with water, diluted with EtOAc, the layers separated and the organics washed with brine, dried (MgSO₄), filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography (SiO₂, 0% to 50% EtOAc in heptane) to afford the protected triazole (30.0 g, 95%) [LCMS Method G, ret time=1.07 min, mol ion=355.9, 357.9].

To a solution of the protected triazole (9.00 g, 25.2 mmol) in NMP (4 mL) were added potassium carbonate (8.71 g, 63 mmol) and 1-(4-methoxyphenyl)methanamine (3.44 mL, 26.3 mmol). The reaction mixture was stirred at 140° C. for 2 hours in a sealed vial. The reaction mixture was diluted with ethyl acetate, washed with brine, the organic layer dried (MgSO₄) and concentrated under vacuum. The crude residue was purified by flash column chromatography (SiO₂, 0% to 100% EtOAc) in heptane to afford R-24 (9.6 g, 78%) [LCMS Method G, ret time=1.35 min, mol ion=414.8].

To a solution of R-24 (7.31 g, 16.1 mmol) in DMF (80 mL) was added sodium hydride (60% in oil, 650 mg, 16.2 mmol) portionwise and the reaction mixture was stirred at room temperature under nitrogen for 15 min. R-13 (2.91 mL, 16.2 mmol) was added and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was washed with water, separated through a hydrophobic frit and the retained aqueous washed with DCM and separated. The combined organics were concentrated under vacuum. The crude residue was purified by flash column chromatography (SiO₂, 0% to 100% EtOAc in heptane) to afford the intermediate amide (5.4 g, 52%) [LCMS Method G, ret time=1.26 min, mol ion=579.1, 581.1].

A solution of the intermediate amide (500 mg, 0.862 mmol) and (2-methoxy-4-pyridyl)boronic acid (132 mg, 0.862 mmol) in 2M potassium carbonate (1.3 mL, 2.60 mmol) and 1,4-dioxane (2.6 mL) was degassed with nitrogen for 5 minutes before adding cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (75 mg, 0.102 mmol). The reaction mixture was stirred at 100° C. in a sealed tube for 10 hours. The reaction mixture was washed with brine, separated through a hydrophobic frit and the retained aqueous washed with further DCM and further separated. The combined organics were concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO₂, 0% to 100% EtOAc in heptane) to afford the intermediate pyridine (140 mg, 26%) [LCMS Method G, ret time=1.14 min, mol ion=608.3].

To a solution of the intermediate pyridine (141 mg, 0.23 mmol) in (1:1) DCM/TFA (1 mL) was added trifluoromethanesulfonic acid (72 μL, 0.46 mmol) and the reaction mixture stirred at room temperature for 1 h. The crude residue was purified by Biotage ISOLUTE® SCX-2 chromatography, eluting with MeOH then 7M NH₃ in MeOH. The ammonia containing fractions were combined and concentrated under vacuum then triturated from acetonitrile/water to afford the title compound (43 mg, 52%).

The following compounds were prepared in similar fashion from the appropriate carboxylic acids and boronic esters or acids: Examples 33, and 42-43, 156, 157, and 217.

Method N: Synthesis of Example 41

To a suspension of R-23 (20.0 g, 88.2 mmol) in THE (200 mL) at 0° C. was added sodium hydride (60% in oil, 3.53 g, 88.2 mmol) portionwise and the reaction mixture was stirred at room temperature under nitrogen for 30 min. The reaction mixture was cooled to 0° C., [2-(chloromethoxy)ethyl](trimethyl)silane (17 mL, 97.0 mmol) was added and the reaction mixture was stirred under nitrogen for 18 h. The reaction was quenched with water and diluted with EtOAc, the layers separated, the organics washed with brine, dried (MgSO₄), filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography (SiO₂, 0% to 50% EtOAc in heptane) to afford the protected triazole (30.0 g, 95%) [LCMS Method G, ret time=1.07 min, mol ion=355.9, 357.9].

A solution of the protected triazole (5.00 g, 14.0 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.87 g, 14.0 mmol) in 2M aqueous potassium carbonate (21 mL, 42.0 mmol) and 1,4-dioxane (30 mL) was degassed with nitrogen for 5 minutes before adding cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (1.03 g, 1.40 mmol). The reaction mixture was stirred at 100° C. in a sealed tube for 2 hours. The reaction mixture was diluted with EtOAc (25 mL) and the organics washed with 1×20 mL saturated brine aqueous solution. The organics were separated, dried (MgSO₄) and concentrated under vacuum. The crude residue was purified via flash column chromatography (SiO₂, 0% to 10% EtOAc in heptane then 0% to 20% MeOH in EtOAc) to afford R-25 (2.80 g, 56%) [LCMS Method G, ret time=0.99 min, mol ion=355.1, 357.1].

A mixture of R-25 (200 mg, 0.563 mmol) and 3-(4-chlorophenyl)propan-1-amine (0.10 mL, 0.62 mmol) were dissolved in anhydrous NMP (1 mL) and potassium carbonate (0.47 g, 3.38 mmol) was added. The reaction mixture was stirred at 140° C. in a sealed tube for 3 hours. The reaction mixture was diluted with EtOAc (10 mL), washed sequentially with water (2×5 mL) and brine (5 mL). The organic phase was dried (Na₂SO₄) and concentrated under vacuum. The crude product was purified by flash column chromatography (SiO₂, 0% to 10% EtOAc in heptane then 0% to 20% MeOH in EtOAc) to afford the protected triazole (60 mg, 22%) [LCMS method G, ret time=1.29 min, mol ion=445] that was dissolved in DCM (1 mL) and trifluoroacetic acid (45 μL, 0.61 mmol) was added. The reaction mixture was stirred at room temperature for 20 hours then concentrated under vacuum. The crude residue was purified by preparative HPLC and freeze dried to afford the title compound (8 mg, 20%).

The following compounds were prepared in similar fashion from the appropriate amine: Examples 28 and 317.

Method O: Synthesis of Example 92

To a mixture of R-14 (300 mg, 1.86 mmol) and N-ethyl-N-isopropyl-propan-2-amine (683 uL, 3.91 mmol) in DCM (2 mL) at 0° C. was added R-14 (312 mg, 1.86 mmol). The reaction mixture was stirred at room temperature for 1 hour then allowed to stand at room temperature for 16 hours. The reaction mixture was diluted with DCM and water, filtered and solid washed with DCM. The solid residue was subsequently heated to 250° C. for 15 min in a sealed vial and then purified by preparative HPLC to afford the title compound (31 mg, 5%).

The following compounds were prepared in similar fashion from the appropriate amine: Examples 7, 160, 164, 165, 166, 183-185, 226, 276, 277, and 296.

Method P: Synthesis of Example 6

R-17 (250 mg, 1.56 mmol) was suspended in anhydrous DMF (1 mL) and 4-nitrophenyl carbonochloridate (76 uL, 1.56 mmol) and N-ethyl-N-isopropyl-propan-2-amine (572 uL, 3.28 mmol) were added. The reaction mixture was stirred at room temperature for 30 min before adding 1-(4-chlorophenyl)-N-methylmethanamine (243 mg, 1.56 mmol) and the reaction mixture was stirred at room temperature for a further 30 min. The reaction mixture was then stirred at 90° C. for 4 hours. The reaction mixture was diluted with DCM, washed with water, separated through a hydrophobic frit and the retained aqueous layer was washed with DCM and separated. The organics were concentrated under vacuum and the crude residue was heated to 250° C. in a sealed vial for 20 minutes. The crude product was purified by preparative HPLC to afford the title compound (11 mg, 2%).

The following compounds were prepared in similar fashion from the appropriate amine: Examples 174, 216, and 218.

Method Q: Synthesis of Example 99

To a mixture of R-27 (29 uL, 0.54 mmol), R-13 (100 mg, 0.54 mmol) and N-ethyl-N-isopropyl-propan-2-amine (279 uL, 1.60 mmol) in anhydrous DMF (1 mL) was added HATU (304 mg, 0.80 mmol) and the reaction mixture was stirred at room temperature in a sealed vial for 17 hours. After this time, the reaction mixture was diluted with DCM, washed with brine, separated through a hydrophobic frit and the retained aqueous was washed with DCM and separated. The combined organics were concentrated under vacuum then purified by preparative HPLC to afford the title compound (13 mg, 7%).

The following compounds were prepared in similar fashion from the appropriate amine: Examples 100 and 115.

Method R: Synthesis of Examples 98, 110, and 111

To a solution of Example 136 (50%, 295 mg, 0.503 mmol) in anhydrous DMF (1 mL) was added sodium hydride (60% in mineral oil, 60 mg, 1.51 mmol) and the reaction mixture was stirred at room temperature for 15 min. Iodomethane (94 uL, 1.51 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was purified by purified by preparative HPLC to give the title compounds Example 98 (12 mg, 8%), Example 110 (13 mg, 8%), and Example 111 (9 mg, 6%).

The following compounds were prepared in similar fashion from the appropriate amine: Examples 287 and 288.

Method S: Synthesis of Example 82

To a solution of R-14 (269 mg, 1.67 mmol) and R-28 (22 uL, 1.67 mmol) in DMF (4.35 mL) were added N-ethyl-N-isopropyl-propan-2-amine (0.58 mL, 3.34 mmol) and propanephosphonic acid anhydride (50%, 1.5 mL, 2.50 mmol). The reaction mixture was stirred at 100° C. for 20 hours. The reaction mixture was diluted with EtOAc (20 mL) washed sequentially with saturated aqueous sodium bicarbonate (2×10 mL), brine (10 mL), dried (Na₂SO₄) and concentrated under vacuum. The crude was purified by flash column chromatography (SiO₂, 0% to 100% EtOAc in heptane) to afford the Boc-amine (327 mg, 39%) that was dissolved in DCM (3 mL) and TFA (0.45 mL, 6.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours then concentrated under vacuum. The crude residue was purified by preparative HPLC then freeze dried to afford the title compound (42 mg, 20%).

The following compounds were prepared in similar fashion from the appropriate amine: Examples 3, 4, 56, 63, 69, 175, 176, 201, 223, 275, 289, and 290.

Method T: Resolution of Examples 67 and 68

Example 117 (95 mg, 0.30 mmol) was dissolved in a mixture of methanol/acetonitrile and purified by supercritical fluid chromotography on a Chiralpak OD-H, 10×250 mm, 5 μm column eluting with a gradient of 0% to 15% methanol in CO₂ at a flow rate of 15 mL/min to afford the title compounds.

Method U: Resolution of Examples 71 and 72

Example 109 (226 mg, 0.67 mmol) was dissolved in a mixture methanol, acetonitrile, IPA and formic acid and purified by flash column chromatography on a Chiralpak OD-H, 20×250 mm, 5 μm column eluting with methanol at a flow rate of 9 mL/min to afford the title compounds.

Method V: Resolution of Examples 88 and 89

Example 131 (82 mg, 0.257 mmol) was dissolved in a mixture of methanol, IPA and formic acid and purified by flash column chromatography on a Chiralpak AD-H, 20×250 mm, 5 μm column eluting with methanol at a flow rate of 9 mL/min to afford the title compounds.

Method W: Resolution of Examples 90 and 91

Example 132 (21 mg, 0.063 mmol) was dissolved in a mixture of methanol and IPA and purified by flash column chromatography on a Chiralpak AD-H, 20×250 mm, 5 μm column eluting with methanol at a flow rate of 9 mL/min to afford the title compounds.

Example 2. Characterization of Compounds

LCMS methods:

Analytical LC/MS Analysis Method A:

-   -   ESI+/−ion mode 150-850 Da     -   Column: Phenomenex Kinetix-XB C18, Part No. 00D-4498-AN, 2.1×100         mm, 1.7 μm     -   Temperature: 40° C.

Gradient:

Time 0.1% formic acid Flow (min) in water acetonitrile (mL/min) 0 95% 5% 0.6 5.30  0% 100%  0.6 5.80  0% 100%  0.6 5.82 95% 5% 0.6 7.00 95% 5% 0.6

Analytical LC/MS Analysis Method B:

-   -   ESI+/−ion mode 150-850 Da     -   Column: Phenomenex Gemini-NX C18, Part No. OOD-4453-BO, 2.0×100         mm, 3.0 μm     -   Temperature: 40° C.

Gradient:

Time 2 mM aqueous Flow (min) ammonium bicarbonate acetonitrile (mL/min) 0 95% 5% 0.6 5.50  0% 100%  0.6 5.90  0% 100%  0.6 5.92 95% 5% 0.6 7.00 95% 5% 0.6

Analytical LC/MS Analysis Method C:

-   -   ESI+/−ion mode 100-1000 Da     -   Column: Waters UPLC® BEH™ C18, Part No. 186002352, 2.1×100     -   mm, 1.7 μm     -   Temperature: 40° C.

Gradient:

Time 2 mM aqueous Flow (min) ammonium bicarbonate acetonitrile (mL/min) 0 95% 5% 0.6 5.30  0% 100%  0.6 5.80  0% 100%  0.6 5.82 95% 5% 0.6 7.00 95% 5% 0.6

Analytical LC/MS Analysis Method D:

-   -   ESI+/−ion mode 100-1000 Da     -   Column: XBridge C18, 3.5 μm 4.6×50 mm column     -   Temperature: 40° C.

Gradient:

Time 10 mM aqueous Flow (min) ammonium bicarbonate Acetonitrile (mL/min) 0.00 95%  5% 2.0 1.20  5% 95% 2.0

Analytical LC/MS Analysis Method E:

-   -   ESI+/−ion mode 100-1000 Da     -   Column: XBridge SB-C18, 3.5 μm 4.6×50 mm column     -   Temperature: 40° C.

Gradient:

Time 10 mM aqueous Flow (min) ammonium bicarbonate Acetonitrile (mL/min) 0.00 95%   5% 2.0 1.40 5% 95% 2.0 4.30 5% 95% 2.0

Analytical LC/MS Analysis Method F:

-   -   ESI+/−ion mode 100-1000 Da     -   Column: Sunfire C18, 3.5 μm 4.6×50 mm column     -   Temperature: 50° C.

Gradient:

Time 10 mM aqueous Flow (min) ammonium bicarbonate Acetonitrile (mL/min) 0.00 95%   5% 2.0 1.40 5% 95% 2.0 3.00 5% 95% 2.0

Analytical LC/MS Analysis Method G:

-   -   ESI+/−ion mode 100-1000 Da     -   Column: Waters UPLC® BEH™ C18, Part No. 186005297, 1.7 μm     -   2.1×50 mm column     -   Temperature: 40° C.

Gradient:

Time 0.1% formic acid 0.1% formic acid Flow (min) in water in Acetonitrile (mL/min) 0.00 95% 5% 0.9 1.10  0% 100%  0.9 1.35  0% 100%  0.9 1.40 95% 5% 0.9 1.50 95% 5% 0.9

Results are presented in Table 1:

TABLE 1 LCMS RT Mol ion LCMS RT Mol ion Example method (min) (m/z) Example method (min) (m/z) 1 A 1.19 328.1 40 A 2.38 328.1 2 A 1.94 367.1 41 A 1.9 314.2 3 A 0.93 342.2 42 A 1.79 342.2/344.2 4 A 1.68 328, 330 43 A 1.74 343.2/345.2 5 A 2.27 428, 430 44 A 2.05 322.2 6 A 1.74 342.2/344.2 45 A 1.93 346.2/348.1 7 A 1.59 328.2/330.1 46 A 1.98 346.2 8 E 1.36 332 47 A 1.38 318.2 9 E 1.38 331 48 A 1.91 371.2 10 D 1.65 405, 407 49 A 1.18 334.2 11 F 1.33 345 50 A 1.70 353.1 12 A 2.34 335.1 51 A 1.73 354.2 13 A 2.45 347.1 52 C 1.50 335.5 14 A 1.56 311.1 53 A 2.38 329.1 15 A 1.60 312.1 54 A 1.76 333.1 16 A 1.72 330.2 55 A 1.24 328.1 17 A 1.65 329.2 56 B 2.36 343.2/345.2 18 D 1.557 340 57 C 1.30 364 19 A 1.75 329.2 58 A 1.53 336.2 20 A 1.71 327.1 59 D 1.65 361 21 A 1.70 330.1 60 D 1.57 333 22 A 2.24 354.2 61 A 2.73 345.0/347.0 23 A 2.27 354.2 62 C 2.93 361.3 24 A 2.38 334, 336 63 A 1.00 335.3 25 A 2.74 345.2/347.1 64 A 2.36 435.2 26 A 2.53 328.1 65 A 1.64 314.0/316.0 27 A 1.28 342.2 66 A 1.95 332.1 28 A 1.71 316.1 67 A 1.84 320.1 29 A 2.10 370, 372 68 A 1.84 320.1 30 A 2.57 362.2 69 A 1.24 295 31 A 1.70 342.2/344.2 70 A 2.01 395 32 A 2.04 358.2/360.2 71 A 1.63 336.1 33 A 2.26 344.2/346.1 72 A 1.63 336.1 34 D 1.39 362 73 A 1.50 336.1 35 E 1.47 352 74 A 1.10 310.1 36 D 1.63 361 75 A 1.82 360.1 37 A 1.55 311.2 76 A 1.82 335.1 38 A 1.70 384.2 77 A 1 373.1 39 A 1.72 385.2 78 A 2.51 350.3 79 A 1.21 305.1 122 B 1.91 348.3 80 A 1.27 351.1 123 B 1.98 334.2 81 A 1.81 334 124 A 2.06 362.1 82 A 0.93 343.1 125 A 1.60 312.1 83 B 2.00 309.2 126 A 1.16 372.1 84 A 1.25 329.1 127 A 1.54 324.2 85 A 1.58 363 128 B 1.69 298.3 86 A 1.54 363 129 A 2.01 322.2 87 A 1.37 364 130 A 2.06 344.1 88 A 1.84 320.1 131 A 1.84 320.1 89 A 1.84 320.1 132 A 2.03 334.1 90 A 2.03 334.1 133 A 0.9 298.2 91 A 2.03 334.1 134 A 2.14 300.3 92 A 1.67 329.1/331.0 135 A 1.21 266.2 93 A 1.68 308.1 136 A 1.86 328.1/330.0 94 A 1.68 308.1 137 A 1.85 328.1/330.1 95 A 1.68 308.1 138 A 1.81 328.1/330.1 96 A 1.89 322.1 139 A 1.79 308.2 97 A 1.74 344.1 140 A 1.78 308.2 98 A 1.88 308.1 141 A 1.75 308.2 99 A 2.13 344.0/346.0 142 A 1.73 308.2 100 A 2.39 329.1/331.0 143 A 1.29 280.2 101 A 2.13 362.0/364.0 144 A 0.52 203.8 102 A 1.73 330.0 145 A 1.37 296.1 103 A 1.49 306.1 146 A 1.52 294.1 104 A 1.71 306.1 149 A 1.93 324.2 105 A 1.93 374.0 150 A 1.18 349.2/351.2 106 A 1.13 329.1 151 A 1.45 360.1/362.1 107 A 1.65 324.1 152 A 2.38 348.1/350.1 108 A 1.57 324.1 153 A 1.16 326.2 109 A 1.63 336.1 154 A 2.47 360.1/362.1 110 C 2.24 308.2 155 A 2.39 342.1/344.1 111 C 2.13 308.2 156 A 2.35 329.1/331.1 112 c 0.95 295.2 157 A 2.83 334.1/336.1 113 A 1.90 346.1/348.0 158 A 2.82 440.1/442.1 114 A 1.78 327.1/329.1 159 A 1.67 333.1/335.1 115 A 2.62 345.0/347.0 160 D 1.48 329 116 A 1.65 306.1 161 H 1.08 406 117 A 1.84 320.1 162 E 1.39 331 118 A 1.97 384.1 163 D 1.54 331 119 A 1.14 319.1 164 D 1.59 343 120 A 2.16 378.1 165 E 1.1 330 121 B 2.47 322.3 166 D 1.35 356 167 H 1.66 405 210 D 1.38 355 168 D 1.61 345 211 D 1.46 352 169 D 1.59 332 212 K 1.43 369.1 170 D 1.59 345 213 K 1.43 369.1 171 D 1.38 346 214 E 1.44 383.1 172 K 1.43 369.1 215 E 1.44 383.1 173 K 1.42 383 216 A 1.52 334.2 174 A 1.10 329.1/331.1 217 A 1.96 342.2/344.1 175 A 0.99 360.2 218 A 1.81 368.2/370.2 176 A 0.93 356.2 219 A 1.38 356.2/358.2 177 D 1.53 346 220 A 1.98 368.2/370.2 178 D 1.3 347 221 A 1.63 325.2 179 D 1.38 371 222 A 1.75 343.2 180 J 1.67 371 223 A 1.62 357.2/359.2 181 H 1.44 353 224 A 2.10 356.2/358.2 182 H 1.42 367 225 D 1.64 353 183 D 1.54 370.9 226 E 1.17 372 184 E 1.15 372.1 227 H 1.4 367 185 D 1.61 355 228 H 1.2 368 186 I 1.47 352.2 229 I 1.39 413 187 E 1.55 399.1 230 E 1.28 333 188 J 1.84 359 231 H 1.33 384.1 189 D 1.5 332 232 D 1.35 371 190 D 1.29 333.1 233 D 1.36 371 191 D 1.23 334 234 J 1.67 371 192 E 1.4 370.1 235 J 1.67 371 193 H 1.28 371 236 D 1.46 354 194 D 1.49 357 237 D 1.46 368 195 D 1.34 353 238 I 1.77 352 196 H 1.32 355 239 C 2.12 342.2/344.2 197 D 1.65 354 240 C 1.74 341.3 198 E 1.43 341 241 C 2.8 346.3 199 A 1.83 333.2 242 C 1.85 346.3 200 A 2.02 375.2 243 C 1.71 328.3 201 A 1.16 356.2 244 C 2.4 326.3 202 J 1.82 347 245 A 1.56 364 203 E 1.47 381.1 246 A 1.72 339 204 E 1.28 382.1 247 A 1.76 341 205 D 1.28 343 248 A 1.79 341/343 206 E 1.29 370.1 249 A 1.62 343 207 E 1.39 370.1 250 A 1.29 342.1/344.1 208 E 1.42 370 251 A 1.18 339.2 209 E 1.42 370 252 A 1.84 349.2 253 A 1.34 334.1 290 A 1.60 357.2/359.1 254 A 1.60 343.1 291 A 1.86 361.1/363.1 255 A 1.93 349.2 292 A 1.80 359.1 256 A 1.73 396.2 293 A 1.50 391.1/393.1 257 A 2.05 323.1 294 A 1.37 343.1/345.1 258 A 2.08 352.2 295 D 1.6 354 259 A 1.51 330.2 296 D 1.33 356 260 E 1.42 341 297 D 1.35 372 261 A 1.46 376.2 298 D 1.7 367 262 A 1.39 332.2 299 H 1.48 403 263 D 1.43 398 300 E 1.55 363 264 H 1.35 382 301 D 1.5 412 265 H 1.16 383 302 D 1.4 384 266 D 1.37 346 303 E 1.48 381.1 267 A 1.46 328.1/330.1 304 D 1.17 354 268 A 1.68 343.1 305 D 1.48 352 269 A 1.76 343.1/345.1 306 E 1.11 322 270 A 1.72 366.2/368.2 307 E 1.19 340 271 D 1.45 362 308 D 1.64 364.9 272 D 1.38 369 309 D 1.16 385 273 D 1.62 368 310 H 1.24 382 274 A 1.52 350.2 311 H 1.38 382 275 A 1.63 343.1/345.1 312 D 1.41 353 276 D 1.31 372 313 D 1.64 359 277 D 1.32 372 314 D 1.41 360 278 D 1.59 384 315 D 1.63 364 279 D 1.59 384 316 D 1.27 413 280 D 1.42 355 317 H 1.59 395 281 D 1.34 371 318 I 1.71 385.2 282 D 1.35 345.1 319 D 1.51 358 283 H 1.22 355 320 D 1.67 377 284 D 1.58 371 321 D 1.42 383 285 D 1.2 399 322 A 1.26 356.1/358.1 286 D 1.4 371 323 A 1.54 335.2 287 A 1.26 356.2/358.2 324 E 1.53 422.9 288 A 1.43 356.2/358.2 325 D 1.6 370 289 A 1.60 357.2/359.1

Example 3: ARM-SAM-TIR SARM1 IC50 Assay

This Example describes an assay of ARM-SAM-TIR NADase activity and use of this assay to measure the efficacy of compounds of Formula I or Formula I′ to block SARM1 mediated NAD+ cleavage. This assay was optimized in such a way as to characterize the efficacy of the compounds in Formula I or Formula I′ to inhibit SARM1 activity and to calculate an IC50 value for each compound. This assay makes use of full length SARM1, which encompasses the ARM, SAM and TIR domains. As demonstrated herein, expression of this fragment without the autoinhibitory N-terminal domain generates a constitutively active enzyme that cleaves NAD+.

Preparation of ARM-SAM-TIR Lysate (STL)

NRK1-HEK293T cells were seeded onto 150 cm² plates at 20×106 cells per plate. The next day, the cells were transfected with 15 μg ARM-SAM-TIR expression plasmid, SEQ ID NO: 1.

(SEQ ID NO: 1) GCGATCGCGGCTCCCGACATCTTGGACCATTAGCTCCACAGGTATCTTCTTCCCTCTAGTGGTCATAACAGCAGCTTCAG CTACCTCTCAATTCAAAAAACCCCTCAAGACCCGTTTAGAGGCCCCAAGGGGTTATGCTATCAATCGTTGCGTTACACAC ACAAAAAACCAACACACATCCATCTTCGATGGATAGCGATTTTATTATCTAACTGCTGATCGAGTGTAGCCAGATCTAGT AATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGC TGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTG ACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTA TTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTAC ATCTACGTATTAGTCATCGCTATTACCATGCTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTC ACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAAT GTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTA GTGAACCGTCAGATCAGATCTTTGTCGATCCTACCATCCACTCGACACACCCGCCAGCGGCCGCTGCCAAGCTTCCGAGC TCTCGAATTCAAAGGAGGTACCCACcatgGCCATGCATCACCACCACCATCATAGCTCCGGCGTCGACCTCGGCACCGAG AATTTATATTTCCAAAGCGGCCTCAATGATATCTTCGAGGCCCAGAAGATCGAGTGGCACGAGGGCAGCTCCGACCTCGC CGTGCCCGGTCCCGATGGAGGCGGAGGCACTGGTCCTTGGTGGGCTGCTGGCGGCAGAGGCCCTAGAGAAGTGAGCCCCG GTGCTGGCACCGAGGTGCAAGACGCTCTGGAGAGGGCTCTGCCCGAACTGCAGCAAGCTCTGTCCGCTTTAAAGCAAGCT GGAGGAGCTAGAGCCGTCGGCGCCGGACTGGCCGAAGTGTTCCAGCTCGTGGAGGAAGCTTGGTTATTACCCGCTGTGGG AAGAGAGGTCGCCCAAGGTCTGTGTGACGCCATTCGTCTGGACGGAGGTTTAGACTTATTACTGAGGCTGCTGCAAGCTC CCGAACTGGAGACAAGGGTCCAAGCTGCTCGTCTGCTGGAGCAGATCCTCGTGGCCGAGAATCGTGACAGAGTGGCTAGA ATCGGTTTAGGCGTCATCCTCAATTTAGCCAAAGAGAGGGAGCCCGTTGAGCTGGCCAGAAGCGTCGCTGGCATCCTCGA GCACATGTTCAAGCATTCCGAGGAGACTTGTCAGAGACTGGTCGCCGCCGGAGGACTCGATGCTGTTTTATACTGGTGCA GAAGGACAGACCCCGCTTTACTGAGGCATTGTGCTCTGGCCCTCGGCAATTGCGCTTTACATGGAGGCCAAGCCGTCCAG AGAAGGATGGTGGAGAAAAGAGCCGCCGAGTGGCTGTTCCCTTTAGCCTTCTCCAAAGAAGACGAACTGTTACGTCTGCA TGCTTGTCTCGCTGTCGCTGTTTTAGCCACCAACAAGGAGGTGGAAAGGGAAGTGGAAAGAAGCGGAACACTGGCTTTAG TCGAACCTCTGGTGGCTTCTTTAGATCCCGGAAGGTTTGCCAGATGTCTGGTCGACGCCAGCGATACCTCCCAAGGAAGA GGCCCCGACGATCTCCAGAGACTGGTGCCTCTGCTGGACAGCAATCGTCTGGAGGCCCAATGTATTGGCGCCTTCTATCT CTGCGCCGAAGCCGCCATCAAGTCTTTACAAGGTAAGACCAAGGTGTTCTCCGACATTGGAGCCATCCAATCTTTAAAGA GGCTGGTGAGCTATTCCACCAACGGCACAAAAAGCGCTTTAGCCAAAAGAGCTTTAAGACTGCTGGGCGAAGAGGTGCCT AGGCCCATTTTACCTTCCGTGCCTAGCTGGAAGGAGGCCGAGGTGCAGACTTGGCTGCAGCAGATCGGCTTTAGCAAATA TTGCGAATCCTTTAGGGAGCAGCAAGTTGACGGCGATTTATTATTAAGGCTGACCGAGGAAGAGCTCCAGACAGATTTAG GCATGAAAAGCGGCATCACTCGTAAGAGGTTCTTTCGTGAGCTCACCGAACTGAAGACCTTCGCCAACTACTCCACTTGT GATCGTAGCAATTTAGCTGATTGGCTCGGATCCCTCGATCCCAGATTTCGTCAGTACACCTATGGACTCGTCTCTTGTGG ACTGGACAGATCTTTACTGCATCGTGTGAGCGAGCAACAGCTGCTGGAAGATTGCGGCATCCATTTAGGAGTGCACAGAG CCAGAATTCTGACCGCCGCTAGAGAGATGCTGCATTCCCCTCTCCCTTGTACCGGAGGCAAGCCTAGCGGAGACACCCCC GACGTGTTCATCAGCTATCGTAGAAACAGCGGAAGCCAGCTGGCCTCTTTACTGAAGGTCCATTTACAGCTGCACGGATT TAGCGTCTTCATCGACGTGGAGAAACTGGAGGCTGGCAAGTTCGAGGACAAGCTGATCCAGTCCGTGATGGGCGCTAGGA ATTTCGTTTTAGTGCTCAGCCCCGGCGCTCTGGATAAATGCATGCAAGATCATGACTGTAAGGACTGGGTCCACAAGGAA ATCGTGACCGCTCTGTCTTGTGGCAAGAACATCGTCCCCATCATCGACGGCTTCGAATGGCCCGAGCCTCAAGTTCTCCC CGAAGATATGCAAGCTGTTTTAACCTTCAATGGAATCAAGTGGAGCCACGAGTACCAAGAAGCCACAATCGAGAAGATCA TTCGTTTTCTGCAAGGTAGATCCTCCAGAGATTCCTCCGCTGGCAGCGACACATCTTTAGAGGGCGCCGCCCCTATGGGT CCTACCTAATAATctagAAGTTGTCTCCTCCTGCACTGACTGACTGATACAATCGATTTCTGGATCCGCAGGCCTCTGCT AGCTTGACTGACTGAGATACAGCGTACCTTCAGCTCACAGACATGATAAGATACATTGATGAGTTTGGACAAACCACAAC TAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATA AACAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTAAAGCAAGTAA AACCTCTACAAATGTGGTATTGGCCCATCTCTATCGGTATCGTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGG GGTTTTTTGTGCCCCTCGGGCCGGATTGCTATCTACCGGCATTGGCGCAGAAAAAAATGCCTGATGCGACGCTGCGCGTC TTATACTCCCACATATGCCAGATTCAGCAACGGATACGGCTTCCCCAACTTGCCCACTTCCATACGTGTCCTCCTTACCA GAAATTTATCCTTAAGGTCGTCAGCTATCCTGCAGGCGATCTCTCGATTTCGATCAAGACATTCCTTTAATGGTCTTTTC TGGACACCACTAGGGGTCAGAAGTAGTTCATCAAACTTTCTTCCCTCCCTAATCTCATTGGTTACCTTGGGCTATCGAAA CTTAATTAACCAGTCAAGTCAGCTACTTGGCGAGATCGACTTGTCTGGGTTTCGACTACGCTCAGAATTGCGTCAGTCAA GTTCGATCTGGTCCTTGCTATTGCACCCGTTCTCCGATTACGAGTTTCATTTAAATCATGTGAGCAAAAGGCCAGCAAAA GGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGAC GCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCT CCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACG CTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCT GCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAAC AGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAAC AGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCA CCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATC TTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTT CACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACC AATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCATTTAAATTTCCGAACTCT CCAAGGCCCTCGTCGGAAAATCTTCAAACCTTTCGTCCGATCCATCTTGCAGGCTACCTCTCGAACGAACTATCGCAAGT CTCTTGGCCGGCCTTGCGCCTTGGCTATTGCTTGGCAGCGCCTATCGCCAGGTATTACTCCAATCCCGAATATCCGAGAT CGGGATCACCCGAGAGAAGTTCAACCTACATCCTCAATCCCGATCTATCCGAGATCCGAGGAATATCGAAATCGGGGCGC GCCTGGTGTACCGAGAACGATCCTCTCAGTGCGAGTCTCGACGATCCATATCGTTGCTTGGCAGTCAGCCAGTCGGAATC CAGCTTGGGACCCAGGAAGTCCAATCGTCAGATATTGTACTCAAGCCTGGTCACGGCAGCGTACCGATCTGTTTAAACCT AGATATTGATAGTCTGATCGGTCAACGTATAATCGAGTCCTAGCTTTTGCAAACATCTATCAAGAGACAGGATCAGCAGG AGGCTTTCGCATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTGCCTTCCTGTTTTTGCTC ACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGAAGATCAGTTGGGTGCGCGAGTGGGTTACATCGAACTGGATCTCAAC AGCGGTAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGCTTTCCAATGATGAGCACTTTTAAAGTTCTGCTATGTGGCGC GGTATTATCCCGTATTGACGCCGGGCAAGAGCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTATT CACCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATTATGCAGTGCTGCCATAACCATGAGTGATAAC ACTGCGGCCAACTTACTTCTGACAACGATTGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCATGT AACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACCAAACGACGAGCGTGACACCACGATGCCTGTAGCAA TGGCAACAACCTTGCGTAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAGTTGATAGACTGGATGGAG GCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGGTGA GCGTGGGTCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGTAGTTATCTACACGACGGGGA GTCAGGCAACTATGGATGAACGAAATAGACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACCGATTCTA GGTGCATTGGCGCAGAAAAAAATGCCTGATGCGACGCTGCGCGTCTTATACTCCCACATATGCCAGATTCAGCAACGGAT ACGGCTTCCCCAACTTGCCCACTTCCATACGTGTCCTCCTTACCAGAAATTTATCCTTAAGATCCCGAATCGTTTAAACT CGACTCTGGCTCTATCGAATCTCCGTCGTTTCGAGCTTACGCGAACAGCCGTGGCGCTCATTTGCTCGTCGGGCATCGAA TCTCGTCAGCTATCGTCAGCTTACCTTTTTGGCA.

The cultures were supplemented with 1 mM NR at time of transfection to minimize toxicity from ARM-SAM-TIR overexpression. Forty-eight hours after transfection, cells were harvested, pelleted by centrifugation at 1,000 rpm (Sorvall ST 16R centrifuge, Thermo Fisher), and washed once with cold PBS (0.01 M phosphate buffered saline NaCl 0.138 M; KCl 0.0027 M; pH 7.4). The cells were resuspended in PBS with protease inhibitors (cOmplete™ protease inhibitor cocktail, Roche product #11873580001) and cell lysates were prepared by sonication (Branson Sonifer 450, output=3, 20 episodes of stroke). The lysates were centrifuged (12,000×g for 10 min at 4° C.) to remove cell debris and the supernatants (containing ARM-SAM-TIR protein) were stored at −80° C. for later use in the in vitro ARM-SAM-TIR NADase assay (see below). Protein concentration was determined by the Bicinchoninic (BCA) method and used to normalize lysate concentrations.

ARM-SAM-TIR IC50 Assay of Formula I or or Formula I′ Compounds.

The enzymatic assay was performed in a 384-well polypropylene plate in Dulbecco's PBS buffer in a final assay volume of 20 μL. ARM-SAM-TIR lysate with a final concentration of 5 μg/mL was pre-incubated with the respective compound at 1% DMSO final assay concentration over 2 h at room temperature. The reaction was initiated by addition of 5 μM final assay concentration of NAD+ as substrate. After a 2 hr room temperature incubation, the reaction was terminated with 40 μL of stop solution of 7.5% trichloroactetic acid in acetonitrile. The NAD+ and ADPR concentrations were analyzed by a RapidFire High Throughput Mass Spectrometry System (Agilent Technologies, Santa Clara, Calif.) using an API4000 triple quadrupole mass spectrometer (AB Sciex Framingham, Mass.).

Results are presented below in Table 2. Compounds having an activity designated as “A” provided an IC₅₀<5 μM; compounds having an activity designated as “B” provided an IC₅₀ 5-15 μM; compounds having an activity designated as “C” provided an IC₅₀ 15.01-30 μM; compounds having an activity designated as “D” provided an IC₅₀>30 uM; nd: not determined.

TABLE 2 SARM1 SARM1 SARM1 Example IC₅₀ (μM) Example IC₅₀ (μM) Example IC₅₀ (μM) 1 A 42 D 83 B 2 A 43 A 84 A 3 A 44 A 85 B 4 A 45 A 86 A 5 A 46 A 87 A 6 A 47 A 88 A 7 A 48 A 89 B 8 A 49 D 90 A 9 A 50 A 91 A 10 A 51 D 92 A 11 A 52 D 93 C 12 A 53 A 94 C 13 A 54 A 95 B 14 A 55 A 96 B 15 A 56 A 97 A 16 A 57 C 98 B 17 A 58 B 99 B 18 A 59 A 100 D 19 A 60 A 101 A 20 A 61 A 102 B 21 A 62 A 103 C 22 A 63 D 104 B 23 A 64 D 105 A 24 A 65 A 106 A 25 A 66 A 107 A 26 A 67 A 108 B 27 A 68 B 109 A 28 D 69 B 110 D 29 A 70 D 111 D 30 A 71 A 112 C 31 A 72 A 113 A 32 A 73 B 114 A 33 D 74 D 115 D 34 A 75 A 116 B 35 B 76 D 117 A 36 A 77 C 118 A 37 A 78 B 119 A 38 D 79 B 120 A 39 D 80 C 121 C 40 A 81 A 122 C 41 D 82 A 123 C 124 A 167 A 210 A 125 A 168 A 211 A 126 C 169 A 212 A 127 A 170 A 213 A 128 D 171 A 214 A 129 A 172 A 215 A 130 D 173 A 216 A 131 A 174 A 217 A 132 A 175 A 218 A 133 D 176 A 219 A 134 B 177 A 220 B 135 B 178 A 221 A 136 A 179 A 222 A 137 A 180 A 223 A 138 A 181 A 224 B 139 A 182 A 225 A 140 A 183 B 226 A 141 A 184 B 227 A 142 B 185 A 228 A 143 C 186 A 229 A 144 D 187 A 230 A 145 D 188 A 231 A 146 A 189 A 232 A 147 D 190 A 233 A 148 nd 191 A 234 A 149 C 192 A 235 B 150 A 193 A 236 A 151 A 194 A 237 A 152 A 195 A 238 A 153 A 196 A 239 A 154 A 197 A 240 B 155 A 198 A 241 B 156 A 199 B 242 B 157 A 200 A 243 B 158 A 201 A 244 B 159 A 202 A 245 B 160 A 203 A 246 A 161 B 204 B 247 B 162 A 205 A 248 A 163 A 206 A 249 A 164 A 207 A 250 A 165 A 208 A 251 B 166 A 209 A 252 B 253 B 278 A 303 A 254 B 279 A 304 A 255 B 280 A 305 A 256 B 281 A 306 A 257 B 282 A 307 A 258 B 283 A 308 A 259 B 284 A 309 A 260 nd 285 A 310 A 261 A 286 A 311 A 262 A 287 A 312 A 263 A 288 B 313 A 264 A 289 A 314 A 265 A 290 A 315 B 266 A 291 A 316 A 267 B 292 A 317 B 268 A 293 A 318 A 269 A 294 A 319 A 270 A 295 A 320 A 271 A 296 A 321 A 272 A 297 A 322 A 273 A 298 A 323 B 274 A 299 A 324 B 275 A 300 A 325 A 276 B 301 A 277 A 302 A

Example 4: Axonal Degeneration Index

This Example illustrates an in vitro axon degeneration assay used to characterize compounds of Formula I or Formula I′. This assay was used to test the efficacy of the compounds of Formula I or Formula I′ to prevent axonal degeneration in a mouse dorsal root ganglion (DRG) drop culture.

Mouse DRG Drop culture: Mouse dorsal root ganglion neurons (DRGs) are dissected out of E12.5 CD1 mice (50 ganglion per embryo) and incubated with 0.5% Trypsin solution containing 0.02% EDTA (Gibco) at 37° C. for 15 min. The cells are then triturated by gentle pipetting and washed 3 times with DRG growth medium (Neurobasal medium (Gibco) containing 2% B27 (Invitrogen), 100 ng/ml 2.5S NGF (Harland Bioproducts), 1 mM 5-fluoro-2′deoxyuridine (Sigma), penicillin, and streptomycin). Cells are suspended in the DRG growth medium. DRG drop cultures are created by spotting 5000 cells/well into the center of each well of a 96-well tissue culture plate coated with poly-D-Lysine (0.1 mg/ml; Sigma) and laminin (3 mg/ml; Invitrogen). Cells are allowed to adhere to the plates in a humidified tissue culture incubator (5% CO₂) for 15 min and then DRG growth medium was gently added (100 ml well).

Axon degeneration assay: Axonal degeneration is stimulated either by manual axonal transection using a scalpel blade, or chemotoxic stimuli. After an appropriate experimental time period, the DRG cultures are fixed in 1% PFA plus sucrose and kept in the fridge prior to imaging. Bright-field images of DRG axons and cell bodies are collected using the 20× water immersion lens of a Phenix automated confocal microscope (PerkinElmer) and quantitation of axonal performed using in-house developed scripts (Acapella, PerkinElmer). 

1-34. (canceled)
 35. A compound which is:

or a pharmaceutically acceptable salt thereof.
 36. The compound according to claim 35 which is:

37-39. (canceled)
 40. A pharmaceutical composition, comprising a compound of formula:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 41-42. (canceled)
 43. A method of treating or preventing axonal degeneration, comprising administering to a subject in need thereof a compound of formula:

or a pharmaceutically acceptable salt thereof. 44-47. (canceled)
 48. The method according to claim 43 wherein the axonal degeneration is associated with a neurodegenerative disease or disorder.
 49. The method according to claim 48 wherein the neurodegenerative disease or disorder is diabetic neuropathy, and chemotherapy-induced peripheral neuropathy.
 50. The method according to claim 48 wherein the neurodegenerative disease or disorder is chemotherapy-induced peripheral neuropathy. 51-53. (canceled) 